That theory has been around the block but it is in fashion again.   In 2009, David Kessler’s book, “The End of Overeating” put forward the thesis that food in contemporary American food has been deliberately engineered–by adding fat, sugar and salt–to exploit our neurochemistry and hijack our free will.

More recently, one of the luminaries of the Paleo movement, Stephan Guyenet, has formulated his own version of this theory, in a compelling series on his Whole Health Source blog, arguing that  ”food reward” is a main driver of obesity. His prescription:  eat a bland diet. Guyenet’s talk about this at the Ancestral Health Symposium last month is the buzz of the paleosphere.

But I think the theory is wrong, for the simple reason that it too blindly takes correlation for causation. And in doing so, it gets the causal direction mostly wrong. We don’t get fat because food has become too tasty. Rather, to a large extent, it is the metabolism and dietary habits of the obese that make food taste too good to resist, leading to insatiable appetites. And the good news is that we are not consigned to blandness.  If we eat and exercise sensibly, we can eat flavorful, delicious foods and enjoy life, without packing on the pounds.

Brain chemistry. Stephan Guyenet’s series on food reward, like Kessler’s book, pins the blame for obesity largely on the increased availability of more palatable “high reward” food.

According to USDA data, Americans today eat an astonishing 425 more calories per day than they did in 1970.  That is the reason for the obesity epidemic, plain and simple.  However, that fact doesn’t tell us why we’re eating more calories, so its usefulness is limited. The increase in calorie intake has come primarily from refined carbohydrate, but even that doesn’t get us very far, because why did we decide to eat more refined carbohydrate?  Probably because of the systematic efforts of commercial food manufacturers to increase the palatability/reward value and availability of processed food.  In the last four decades, the US has become saturated with hyperpalatable/rewarding commercial and restaurant foods including fast food, soda, french fries, chips, candy and other industrial products.  I’ve seen people claim that they ate these things just as much in the 1960s and 70s, but the USDA and National Restaurant Association data show otherwise.  The qualitative changes in the US diet have been swift and profound… (A Roadmap to Obesity, August 25, 2011)

But what is it about food that makes it rewarding or not?  Guyenet suggests that food reward relates to opioid and dopamine signaling:

Feeling satisfied after eating something is not reward. If you keep eating a starch food beyond what’s appropriate, that is probably because it has too much reward/hedonic value for you. Opioid signaling, implicated in hedonic processing, shuts off satiation signals in the brain and may also increase the setpoint. Dopamine signaling, implicated in reward, can strongly influence food intake and also seems to be able to increase the set point.

In “The End of Overeating”, Kessler also emphasizes the way that “hyperpalatable” foods stimulate dopamine, opioids and other reward neurotransmitters.  To be fair, both Guyenet and Kessler acknowledge that food reward is not the only explanation for obesity.  They acknowledge the role of genetics, exercise and other factors.  But for both of them too-tasty food is the leading culprit.

The relativity of taste.  But is it really that simple?  Are some foods inherently and invariably rewarding? Do our taste buds and noses directly respond to tasty foods or foods high in fat, sugar or salt by stimulating the secretion of dopamine and opioids in the brain, turning us into addicts? Somehow, it must be more complex than that.

Seth Roberts has postulated a different explanation, in which learning plays a role. His Shangri-La Diet was derived from observations that tasty foods lead to weight gain only after repeatedly encountering the flavor and the calories together. Roberts calls this process “flavor-calorie association”.  It’s a Pavlovian conditioning process: the more habitual the association, the greater the obesogenic potential of the food or beverage.  So his diet involves regular doses of “flavorless calories” in the form of bland oils, sugars or proteins.  Alternative strategies include consuming foods with unfamiliar flavors or “crazy spices”, or flavored noncaloric beverages like herb teas. (For more on flavor-calorie association, see my post on Flavor Control Diets).

Some foods and flavors may be naturally appealing to infants and children, but there is strong evidence that food preferences vary considerably among individuals and cultures.  ”One man’s food is another man’s poison”. Roberts describes the interesting story of a Gaku Homma, Japanese cookbook author whose initial impression of Coke was  that it tasted “like medicine” and was repulsed by it. Similarly, Westerners are often repulsed by Asian fermented foods, or delicacies like dog or snake. Certain cultures find insects and grubs to be delectable, but most of us would probably pass, even knowing that such foods represent a nutritious source of calories.  There are many unfamiliar foods, rich in fat, sugar, salt or flavor, that the average fan of potato chips and ice cream would reject, even if hungry. For an interesting discussion of the cultural relativity of food acceptance and rejection of unfamiliar or novel foods, see the article by  John Prescott in the Encyclopedia of Food and Culture.

Likewise, over time we can learn to like flavors and tastes that were once unappealing.  Roberts cites experiments where rats that do not like the taste of saccharine, grow to like it when they are intravenously fed glucose.  There are many “acquired tastes” that we come to like only after repeated exposures.  Our palates are changeable.

If you think that food aromas are naturally or inherently appetizing, rather than relative, ask yourself: Why do we respond to food odors differently than other evocative and pleasant odors – flowers and plants, soil, sea, even pleasant or sensual human scents?  Smelling a rose does not make you hungry. Could we be conditioned to salivate and secrete insulin in response to the smell of a rose if we always sniffed a rose before gulping down a sweet drink? I think so. Pleasant aromas or tastes don’t necessarily generate a drive to eat.  The association between sensation and the drive to eat must be learned.

In fact, both Guyenet and Kessler appear to acknowledge the relativity of taste at certain points in their accounts.  For example, Guyenet notes that taste preferences towards beer or vegetables change as we transition from childhood to adulthood.  It is instructive that Guyenet defines “food reward” in a surprisingly  broad way:

Food reward is the process by which eating specific foods reinforces behaviors that favor the acquisition and consumption of the food in question.  You could also call rewarding food “reinforcing” or “habit-forming”, although not necessarily in an addictive sense.  Food reward is a perfectly normal and healthy part of life, although I believe it can be harmful if it exceeds the bounds of what we’re adapted to.  Food reward is essential for survival in a natural environment, because it teaches you what to eat and how to get it through a trial-and-error process. (Food reward, May 26, 2011)

In this definition of reward, Guyenet seems to move away from the idea that “reward” is an inherent property of food (i.e. fat, sugar, salt) in triggering opioids and dopamine, but rather is a result of conditioning. Sounding very similar to Roberts, Guyenet notes that

Researchers have demonstrated in rodents and humans that pairing a flavor with a source of calories makes us gradually enjoy the flavor more, whether or not it remains paired to calories afterward.  That’s called a “conditioned flavor preference”, and it’s a simple demonstration of food reward in action.  The brain senses the ingested calories and assigns a positive reward value to the cues (flavor, location, etc.) associated with the calories, after which we’ll be more likely to eat something that contains the preferred flavor.

As another example, rats prefer to hang around a place where they have repeatedly received rewarding food.  Have you ever seen a child run after an ice cream truck?  After a certain time, our motivation to obtain a food that we perceive as rewarding increases, and so does our consumption of it.  Rats accustomed to eating human junk food will endure foot shocks and extreme temperatures to obtain it, even when much healthier unprocessed rodent chow is freely available

Put another way:

It doesn’t matter whether or not you like the Little Debbie cake once it’s in your mouth.  It doesn’t matter how you feel afterward.  The only thing that matters is whether or not you’ll buy another one tomorrow.  That’s food reward.

Kessler also acknowledges the role of Pavlovian conditioning in appetite, recognizing that not just flavors, but any cues can serve as reinforcers.  In Chapter 10 of his book, he cites Pavlov’s success in training dogs to salivate in response to the ringing of a bell, even after it is no longer accompanied by food. Kessler discusses Kent Berridge’s related concept of “incentive salience” :

Simply put, incentive salience is the desire, activated by cues, for something that predicts reward.  It’s a learned association — we learn to want a food or some other substance we once liked…Cue-induced wanting, said Berridge is “triggered by the sight of a cookie or someone lighting up a cigarette nearby or clinking the ice cubes in the glass of alcohol…Those kinds of cues have the power to evoke the desire to take that thing again.” Experience imbues the cue with incentive salience. Positive emotions become embedded in cues, which then develop a force of their own. (The End of Overeating, Ch. 10)

So the door has been opened here to the idea that “reward” is not an inherent property of food but rather the consequence of a conditioned association or “pairing” between the calories in the food and a sensible signal or cue.  The cue could be a flavor, but it could just as well be a visual or auditory cue,  a familiar location or a social context.  In this understanding, “reward” not an inherent property of the food, but is rather a learned response to perceptual cues associated with the food.  These cues need only at some point to have become associated with a conditioned expectation of caloric value.

But now we come to the internal contradiction in the Kessler-Guyenet theory of food reward:  Is “reward” objective and invariant — or relative, subjective and variable?  It cannot be both. To say that reward is “relative” means that it varies markedly among individuals and across cultures, but that does not make it any less real.  It can be a powerfully motivating force, driving the obese to overeat and even binge to unhealthful extremes.  But to acknowledge the subjectivity and relativity of food reward is at odds with the idea that there is such thing as inherently “hyperpalatable” food that is irresistibly obesogenic in and of itself.

An alternative explanation: impaired metabolism.  I’m not denying here that people crave or get addicted to foods like potato chips, cookies and ice cream.  No doubt these people find the flavors salient and compelling, even to the point of addiction. But it’s not the flavor that causes the behavior in the first place. The flavor only becomes a strong cue under certain conditions.  That’s obvious from the simple fact that many people, eating the very same foods, do not find them to be addictive.  While I occasionally enjoy a cookie or some ice cream, I actually find it repulsive to eat more than a modest amount.  While I used to like soda, I now experience Coke as sickly sweet.  And I think I’m not alone in that reaction.

A more likely explanation is that food addicts have altered, perhaps even damaged, their metabolisms.   They are most likely insulin-resistant and leptin-resistant as a result of many possible factors, including obesity, stress and inflammation of their insulin receptors and glucose transporters.   Guyenet aptly describes how inflammation and lipotoxicity damage the hypothalamus:

There’s an additional factor that I’ve come to believe may be an “elephant in the room” when it comes to insulin/leptin resistance and chronic inflammation, and that is, ironically, energy excess.  Glucose and fatty acids, the body’s main two fuels, are toxic when present in the bloodstream in excess.  When someone eats too many calories, his body has to deal with the excess.  The healthiest way of doing this is actually to shunt the excess energy into fat tissue where it is inert.  If the fat tissue does not have a sufficient affinity for the excess fat, free fatty acid levels in the circulation may rise, and tissues and cells may accumulate fat and fat metabolites…if fat mass increases enough, fat cells become insulin resistant, release more fatty acids into the circulation and fail to clear fatty acids from the circulation after a mixed meal.  Essentially, fat tissue loses its formerly high affinity for excess fat, and these undesirable fat metabolites accumulate in lean tissues in a manner reminiscent of lipodystrophy.  This contributes to insulin resistance and glucose intolerance by the same mechanism described above, creating an excess of circulating glucose as well, which together with the excess of fatty acids can enhance chronic inflammation, further insulin resistance and damage the insulin-secreting pancreas.

…Therefore, it’s possible that an excess of circulating fatty acids (and perhaps glucose) itself acts to raise the setpoint through the gradual accumulation of fatty acid metabolites and inflammation in the hypothalamus, promoting leptin resistance and creating a “cascading failure” of energy balance regulation, glucose metabolism and inflammatory signaling.  This would explain why people in affluent societies have trouble staying lean as they age, as well as why obesity is so difficult to treat.  I think this is likely to be a late stage process, occurring after significant body fat accumulation and essentially “cementing” the increase in body fatness.  The early stage that causes the initial rise in body fatness probably has more to do with food reward/palatability/availability, although that should remain a factor even after obesity is well established…The basic idea is that in genetically susceptible people, excessive food reward/palatability/availability and inactivity cause overconsumption and an increase in the body fat setpoint, followed by the eventual accumulation of fat metabolites and inflammation in the hypothalamus, which exacerbate the problem and make it more difficult to treat.  Other factors, such as micronutrients, gut flora, fiber, fat quality, polyphenols, sleep and stress, may also play a role.  I think this is a reasonable working hypothesis of why obesity has increased so rapidly in the last 30 years, and is so difficult to treat once established.  I believe these ideas are broadly consistent with the research and opinions of senior obesity researchers I respect. (Roadmap to Obesity, August 25, 2011)

Cause and effect. Where I believe Guyenet goes wrong in the above passage is in postulating that “the early stage” of obesity is driven by primarily by food reward causing overconsumption, which then leads to obesity and leptin resistance.  I think the cause and effect relationship is reversed. Certainly “normal” reward is part of a healthy appetite, but that doesn’t lead to obesity.  It is the leptin resistance of obesity that sets one up for food reward to become pathogenic.   According to Robert Lustig, the normal satiating effect of insulin within the brain (CNS) becomes impaired in those with insulin and leptin resistance:

Although CNS insulin levels tend to reflect serum insulin levels, the relationship breaks down in obesity states. In obesity, there is proportionally less CNS insulin; the expression of the CNS insulin transporter is decreased in several obesity models. This paucity of insulin available for satiety signaling may represent a form of CNS insulin resistance. (Lustig, Fast Food, Central Nervous System Insulin Resistance, and Obesity)

Put simply, it takes more time and larger quantities food or beverage for insulin-resistant individuals to become sated, because the appetite-suppressing or “shut off” effect of insulin in the hypothalamus is impaired.  Added to this is the fact that obese, insulin-resistant individuals typically have a grossly amplified preprandial insulin response, which means that blood glucose is more easily stoked by mere appetite cues like the sight, aroma, or even thought of food.  Frequent, regular and familiar eating of these reward foods further strengthens the reinforcement.  Even stress can trigger this hunger cycle.  This leads to a very strong drive to start eating and great difficulty in shutting off the eating.  And with more overconsumption of food and the resultant obesity, a vicious cycle sets in, leading to heightened insulin-resistance and leptin-resistance.  Once this vicious cycle begins, the psychological component of food cravings and addictions is enhanced.  The association between flavor cues — or any cues — and consumption of the food is strengthened.  And the food becomes more and more palatable, even “hyperpalatable”.  But it is the impaired metabolism of obesity and the reinforcing eating patterns that make these foods hyperpalatable to the individual, not the other way around.

Foods are not inherently hyper-rewarding.  Rather, an impaired metabolism, combined with reinforcing eating patterns  lead to food becoming hyper-rewarding. 

I can anticipate the following objection to my argument:  Am I saying that any food can become hyperpalatable or addictive?  If so, why are foods like french fries, bread, cookies, chocolate and ice cream craved more than celery, cucumbers and lamb chops?   The answer, I think, is that if you are leptin-resistant and insulin-resistant, these high calorie foods provide a sufficiently rapid “bolus” injection of calories into the bloodstream to overcome any initial preprandial drop in blood glucose, and to spike insulin sufficiently high to overcome the CNS insulin resistance and thus satisfy appetite.  However–and this is a key point–not everyone finds junk foods to be irresistable.  Most insulin sensitive individuals are readily sated on pizza or dessert.  And not everyone even finds these foods to be enjoyable.

Another important factor in the addictiveness of food is the reduction or impairment in dopamine receptors in the brains of the obese, as documented by PET scans. Interestingly, a similar reduction in dopamine receptors is seen in drug addicts and depressed individuals.  This could be a result of the overstimulation by raised levels of dopamine from the “bolus” of large meals or binges. resulting in a homeostatic downregulation of receptors.  I’ve discussed this in more detail in my post Change your receptors, change your set point. Probably any large amount of calories, even with unfamiliar, less palatable, or weaker flavors would do the same trick.  For a short time, there would be frustration due to reduced dopamine signaling  — until the brain learned the new flavor-calorie association.

Bland food diet.   From his theory of food reward, Guyenet proposes a way out:  Eat bland foods.  He supports this by citing evidence that pre-industrial cultures such as the Kitavans eat a diet that is quite bland, despite being high in carbohydrates, and thereby they remain lean and healthy.  He references studies on the effects of bland food diets in lean and obese humans (by Hashim and Van Italie, and by Michael Cabanac) to support his thesis.

Investigators have known for decades that the cafeteria diet is a highly effective way of producing obesity in rodents, but what was interesting about this particular study from my perspective is that it compared the cafeteria diet to three other commonly used rodent diets: 1) standard, unpurified chow; 2) a purified/refined high-fat diet; 3) a purified/refined low-fat diet designed as a comparator for the high-fat diet. All three of these diets were given as homogeneous pellets, and the textures range from hard and fibrous (chow) to soft and oily like cookie dough (high-fat). The low-fat diet contains a lot of sugar, the high-fat diet contains a modest amount of sugar, and the chow diet contains virtually none. The particular high-fat diet in this paper  (45% fat, which is high for a rat) is commonly used to produce obesity in rats, although it’s not always very effective. The 60% fat version is more effective.

Consistent with previous findings, rats on every diet consumed the same number of calories over time… except the cafeteria diet-fed rats, which ate 30% more than any of the other groups. Rats on every diet gained fat compared to the unpurified chow group, but the cafeteria diet group gained much more than any of the others. There was no difference in fat gain between the purified high-fat and low-fat diets.

So in this paper, they compared two refined diets with vastly different carb:fat ratios and different sugar contents, and yet neither equaled the cafeteria diet in its ability to increase food intake and cause fat gain. The fat, starch and sugar content of the cafeteria diet was not able to fully explain its effect on fat gain. However, each diets’ ability to cause fat gain correlated with its respective food reward qualities. Refined diets high in fat or sugar caused fat gain in rats relative to unpurified chow, but were surpassed by a diet containing a combination of fat, sugar, starch, salt, free glutamate (umami), interesting textures and pleasant and invariant aromas.

Guyenet’s interpretation is that the rats ate more of the “cafeteria diet” because it was more palatable, presumably due to the higher fat, starch and sugar content, than the equally calorie dense blander diets. But this is not proven.  How do we know it was more “palatable”, if this is a subjective quality?  All we know is that more of the cafeteria diet was consumed.  We can of course define that as palatability, but that would make the argument circular.  The real question is:  Do we eat more calories because inherent “palatability” or taste characteristics?  Or do foods become  perceived as more palatable because of prior food experience, eating patterns and associations that modify neural circuitry and the drive to eat?  Palatability appears not to be something inherent in food, but rather something changeable. We do not know what diets or reinforcement schedules the rats were raised on before Cabanac’s conducted his experiments.

From these and other observations, Guyenet concludes:

Some people may be inclined to think “well, if food tastes bad, you eat less of it; so what!” Although that may be true to some extent, I don’t think it can explain the fact that bland diets affect the calorie intake of lean and obese people differently. To me, that implies that highly rewarding food increases the body fat setpoint in susceptible people, and that food with few rewarding properties allows them to return to a lean state. (Food Reward, A Dominant Factor in Obesity, Part II)

In recognizing that bland diets have different effects on the lean and the obese, Guyenet here seems to made a full retreat from asserting the explanatory power of food reward as a primary driver. The relativity of taste here reveals that it must be a consequence, not a determinant, of metabolism and neural conditioning.

What can we do?  If you believe that tasty food is inherently addictive, it is reasonable to seek out bland food, and avoid strong flavors, fat, sugar and salt.  But is this necessary?  Do we have to give up not just “junk foods” like Big Macs, french fries and ice cream — but also more healthful foods that are flavorful, fatty, sweet or salty? What about lamb curry (fatty and flavored), berries and cream (sweet and fatty) or salted steak?  I think not. Flavor, fat, salt and even a modest amount of sugar is not the seed of obesity.  Rather, it is the effect that foods have on our hormones and receptors that we should think about.  To avoid obesity, we should strive to maximize our insulin sensitivity and leptin sensitivity. This can be done by a variety of measures, discussed elsewhere on this blog, including:

• weight loss, particularly abdominal fat
• intermittent fasting
• avoiding inflammatory foods and toxins that impair receptor sensitivity
• supplementing with fish oil, magnesium and vitamin D for receptor health
• avoiding chronic stress, but pursuing intermittent, intense “good” stress, such as:
• > high intensity exercise
• > cold showers
• > brief thrills and unpleasant challenges

…

Bon apetit.

One of the most common reactions I get to my advice to try intermittent fasting is:  I could never do that!

Like the Jackson Browne song “Running on Empty,” the word “fasting” often conjures up dire images of starvation and energy deprivation.  Many of you reading this post may have experienced strong hunger pangs, headaches, tiredness, sweating and even shaking or wooziness when going without eating for even part of a day, much less a whole day.  So it is natural to extrapolate such experiences into the thought that going without food for a day, or even several hours, would invariably lead to uncomfortable or even dangerous hypoglycermic symptoms. That, together with the negative image of fasting as something unhealthy or associated with eating disorders, leaves most people pale at the thought of even attempting a short fast.

But I tell you, if you don’t try fasting you are missing out on an enjoyable, incredibly energizing experience that will put you in control of your eating and improve your health, your energy and your outlook.  Many people, myself included, have learned to fast for up to a day or even longer, on a regular basis and without negative repurcussions. Done correctly, short-term fasting is not dangerous, it’s actually health-promoting and greatly helps to retrain your appetite.  If you need to lose weight, the fast helps both in reducing basal insulin and retraining your appetite to be smaller. I’ve written about the benefits of intermittent fasting extensively on this site. Many of the Diet Links listed in the right-hand panel, such as fast-5 and Eat-Stop-Eat, amply document the safety and health benefits of fasting, dispelling the myths about “starvation mode”, slowing of metabolism,  and loss of lean muscle mass.  So I won’t reiterate here the voluminous evidence supporting the benefits of intermittent fasting.  Our bodies are designed to last many days with out food, without great discomfort, and in fact it is beneficial to our health to forgo food periodically. But many of you are asking: Am I really up to this?  How do I get started?

To clarify, by intermittent fasting (IF), I mean forgoing eating for at least 12-20 hours in a day, at least one or two days each week. For many of us, it is a daily practice. Water and unsweetened, non-caloric beverages are allowed, but I exclude “juice fasting” or any solid snacks from true fasting. Others have written about the virtues of juice fasts for “detox” or “cleansing”, but IF has a different purpose, namely insulin reduction, appetite reduction, and mental clarity and focus.

Tips for getting started. So this post is not about the benefits of intermittent fasting, but rather about how to get started with it.  I’m basing this largely on my own personal experience, combined with what I’ve learned about what has worked for others. Fasting is not that hard or unpleasant to do. The reality is that, like skydiving, the contemplation of it is probably far worse than the experience.  You will experience some periods of discomfort, but you may be surprised at how great you’ll feel most of the time you are fasting, especially once you are past the first few hours.  People on low carbohydrate diets often (but not always) experience the pleasurable energy that comes with ketosis; I’ve found that the ketosis of fasting is deeper, and more reliable that that from low carb.  Several people who experience brain fog on low carb  find fasting to provide greater clarity and energy.

Here are 7 practical suggestions to help you get through the transition:

1. Start with a mini-fast. How long do you go between meals without eating? Two hours? Five hours? Start there and try to increase it by a few hours. The easiest way to start is to cut out eating anything between dinner and bedtime. Then go to cutting out afternoon snacks 2 or 3 days a week. And increase from there in increments. Of all my suggestions, I think this is the most important. It’s one of the core principles of using Hormetism to improve your strength and resilience in any challenging endeavor. You have to walk before you can run.

A very common mistake that many people make when embarking on fasting is to go straightaway from a typical pattern of 3 meals per day with snacks, to a day-long fast.  That’s a terrible idea, and yet it forms the main reason that so many people reject fasting as impractical or unhealthful.  I’ll repeat here the comments I made in an earlier post on Calorie restriction and hormesis about a researcher’s conclusions in a 2006 study of calorie restriction in mice, in the journal Biogerontology:

Calorie restriction is doomed to fail, and will make people miserable in the process of attempting it,” said Dr. Jay Phelan, an evolutionary biologist at the University of California, Los Angeles, and a co-author of the paper. “We do see benefits, but not an increase in life span.” Mice who must scratch for food for a couple of years would be analogous, in terms of natural selection, to humans who must survive 20-year famines, Dr. Phelan said. But nature seldom demands that humans endure such conditions. Besides, he added, there is virtually no chance Americans will adopt such a severe menu plan in great numbers. “Have you ever tried to go without food for a day?” Dr. Phelan asked. “I did it once, because I was curious about what the mice in my lab experienced, and I couldn’t even function at the end of the day.

It’s not surprising that Dr. Phelan’s personal “one day experiment” failed and that he “couldn’t function” after suddenly downshifting gears so rapidly. As anyone who has taken the time to research calorie reduction or intermittent fasting realizes, a dietary change of this sort should be approached gradually, allowing time for deconditioning of previous dietary habits and hormonal responses. These changes typically take weeks or longer to become comfortable. But that does not mean that a reduced calorie diet is “extreme”. By historical standards, it would be more accurate to characterize the typical hypercaloric American diet as extreme.

2.  Schedule your fasts. Intermittent fasting works best when you are in control of the timing.  I like being able to spontaneously decide when I’ll start my next fast and I plan exactly when I’ll break the fast and eat.  That really frees me from thinking about food and making choices, because I know that at 4 p.m. Friday or noon Sunday I’ll have my next meal. Associating the start and stop of a planned fast with definite events or times of day takes advantage of the well-known behavioral principle of “putting on cue”.  For a fuller explanation, check out the work of Karen Pryor, the renowned animal behaviorist and dolphin trainer.  I’ve also written about this on the Psychology page of this blog.

3. Cheat using high fat “training snacks”. If you’re having trouble fasting, it is likely that you are lacking the ability to readily shift to fat burning and ketosis.  When you are fasting, after initially depleting your glycogen stores, you will be literally “living off your fat”, as well as fat byproducts like ketones.  To do that, you’ll need to get your insulin level very low and upregulate your catabolic hormones and enzymes: glucagon, adrenaline and hormone sensitive lipase.  But if you are used to eating 3 or more meals and snacking frequently, then you are not used to metabolizing your own fat stores, and you have difficulty shifting quickly from energy storage (anabolism) to energy release (catabolism) .  You literally have weeks of “meals” stored beneath your skin and within your abdomen.  You just can’t access them.  It’s literally like having a locked pantry on your body, so when you get hungry you have to eat food supplied externally, instead of what is already within you.

So train yourself to burn fat by eating pure fat or oil!  The easiest way to train your body to get it used to burning fat, is to “jump start” it with a small high-fat “training snack”.   You don’t need much to get started: 5 to 10 grams of fat is plenty.  Don’t worry, this is not a “high fat diet”, it serves only to provide some satiety and let your metabolism get used to fat burning. The amount of fat you’ll snack on is trivial compared to your overall weekly diet, and you’ll go back to your “normal” diet after the fast. The best approach is to wait until you would normally have a meal or snack and substitute the high fat training snack.  This will tend to suppress your appetite for at least a few hours.  If you start to get hungry again, take another training snack — but wait at least 3-4 hours between these snacks. The training snacks must be virtually free of any carbohydrates or protein and must be small.  Good examples include:

• “Carbless cream soda”. Pour a few tablespoons of heavy whipping cream into a glass (check to make sure it has less than 1 gram carbs) over ice cubes and add sparkling water or herbal tea.
• “Platinum” tea or coffee. To an unsweetened cup of hot tea or coffee, add a tablespoon or two of heavy whipping cream or coconut oil.  The heavy cream has the advantage of easily blending with the tea or coffee, but some people find the coconut oil to be more energizing.  It comes as a solid but readily melts in the hot beverage; it tends leave some oily droplets on the surface because it does not emulsify as well as cream, but most people have no problem with that.  It is important not to add any sweeteners; even artificial sweeteners will tend to psychologically induce a conditioned preprandial insulin response (See Diet page).
• Macademia nuts.  These are high in fat with very few carbs.  Eat no more than a half dozen.
• A small piece of cheese. This is a great training snack, but keep it to one or two small slices of cheese.
• A tablespoon of oil. It may not sound very palatable, but a spoonful or two of extra light olive oil or other vegetable oil can be a great appetite suppressant and kick you into fat burning mode rather effortlessly. The oil works best if flavorless, or if you pinch your nose to avoid tasting it before rinsing.  This is the basis for the popular Shangri-La Diet of Seth Roberts. Roberts attributes the effect to breaking the connection between flavor and calories.  I propose an alternative explanation in my post on Flavor Control Diets.  and also in a long discussion thread on the Shangri-la Diet forum. In any case, flavorless or not, a small dose of oil is a very effective “bridge” to fasting.

4.  Savor flavored calorie-free beverages. To satisfy your need for flavor, enjoy herb teas and black coffee.  Decaf is preferable, but if you have a caffeine habit, go with it for now.  Don’t add any sugar or artificial sweeteners, since these can induce an insulin response that shuts down fat burning. Flavored beverages are a great boon to fasting because they satisfy the urge for flavor and provide some pleasure that can be a big help.

5.  Smell something aromatic while fasting. This is an old aromatherapy trick to turn off your appetite, but it has a scientific basis.  A strong aroma from herbs, spices, flowers or perfumes can rapidly dampen a craving by saturating the cephalic phase insulin response, as explained in my post on Flavor control diets — but you must not eat within 30 minutes after smelling. It is also useful to repeat the smelling frequently and cycle between very different aromas. This has been exploited in devices such as the SlimScents odor inhaler, but a few minutes with your spice rack, perfume bottles or flower garden may do the trick.  The good news is that the effect is long lasting and will permanently decondition your cravings.  Try it!

6.  Drink water frequently. This is an old standby and may seem boring compared to the above two suggestions.  But it works well in two ways: it tends to suppress hunger, and it keeps you hydrated. Keep in mind that the effect is often delayed, so wait 15-30 minutes after drinking the water before you pass judgement on it.

7.  Exercise briefly when hungry or tired. This is one of the more surprising ways to fight cravings, tiredness, mental fog, or borderline hypoglycemia. It may seem counterintuive to expend energy just at the point you are feeling hungry or tired. But it works incredibly well! The key is to do it at the first sign of a cranky or tired feeling, and you’ll head off it off at the pass.  By “exercise” I don’t necessarily mean going to the gym — unless you are used to that. Walking around for 5-15 minutes at a brisk pace is good enough, particularly if you can elevate your heart rate a bit. If you have been fasting, walking or other brief exercise will stimulate your liver to release glucose and free fatty acids, giving you an energy boost. It really is just about as good as eating a meal, for providing energy, and it has the benefit of providing a more sustained form of energy.  You’ll find that “after lunch” meetings are less soporific.

Getting out for a lunch time walk is an excellent alternative to eating lunch.  It gets you away from the kitchen or cafeteria, changes the scene and restores energy.   I probably eat only two lunches a week at work; the other days I go walking either outside or inside, depending on the weather.  Make it social and enlist a friend or start a small walking group – it is just as easy to converse while walking as while eating at a table.

When you get more experienced with fasting, the addition of extended, more intense exercise is very energizing and beneficial. With lower basal insulin levels and upregulated catabolic hormones and enzymes, you’ll find that a long run or workout with weights provides lasting energy and suppresses your appetite. Eating before or after the fast ruins the benefits. Wait at least several hours after the workout before breaking the fast. This may seem paradoxical, as it is virtually the opposite of what many experience who are not used to fasting.  But I have found it to be my experience.  For those interested in fasted workouts, checkout Martin Berkhan’s Leangains blog, as well as a recent article in Running Times on the benefits of glycogen-depleted exercise for greatly increasing your endurance; it appears to be a great strategy for learning to burn fat and weaning yourself off carb dependence,

A final word. The above approach, which emphasizes gradualism, should give your metabolism time to adapt.  For most people, this is enough to avoid any health issues with hypoglycemia or diabetic complications.  In fact, Lee Shurie cured his diabetes, normalized his blood sugar, and increased his energy level by carefully monitoring his blood glucose and gradually transitioning to intermittent fasting.  He found that all the traditional advice to eat low glycemic foods and exercise was insufficient to normal his blood glucose. Eventually, by delaying meal time and allowing his blood glucose to drop into the normal range, he found himself eating only at dinner time, and all the happier for it.  So transition to IF gradually. However, if you have any concerns, stop the fast and eat.  Consult with your physician if you have concerns.  Otherwise, check out the discussion of Intermittent fasting on the Getting Stronger Discussion Forum, to read others’ experiences.

Happy Thanksgiving!

Why is it so hard to make permanent changes to your habits, your health, and your happiness?  Some of the most difficult struggles in life involve losing weight (and keeping it off), overcoming addictions, and recovering from depression. Many diets and therapies deliver great short term results, but the most common pattern appears to be relapse.  It often seems that you are destined to fulfill some biological program — that you are stuck with a high body weight set point or an addictive or depressive personality that cannot be escaped in the long run.

This pessimistic message is prevalent among those who have investigated the track records of the “helping” industries: the weight loss companies, the addiction recovery centers, and the various schools of psychology and psychiatry. Unlike the advocates, those who investigate them often find the results are less than what the practitioners might want you to believe.  In the arena of dieting and weight loss, books such as “The Dieter’s Dilemma” (Bennett and Gurin, 1982), and  ”Rethinking Thin”  (Kolata, 2008) echo the original set point theory first propounded by Gordon C. Kennedy in the 1950s; they conclude that your body weight is largely predetermined by a biological set point that is handed to you at birth, plus or minus about ten pounds. I do agree that sustained weight loss cannot be achieved through sheer will power alone, or simply by using diet and exercise in order to create a calorie deficit. Yet, while there is some plausibility to the set point theory, I am convinced that it is wrong because it overlooks some important factors. I’ve already given some of my reasons for my disagreement with set point theory in other posts on this blog (Flavor control diets, How to break through a plateau). But in this post I’ll present some strong evidence for an alternative theory, based on the homeostatic regulation of cellular receptors for hormones and neurotransmitters. This is a variable set point theory which I call the receptor control theory. This theory proposes a mechanism that controls appetite and body weight, as well as regulating the balance of  energy and pleasure in your life. It provides practical tools to lose weight and keep it off, overcome addictions without relapse, and move out of depression into happiness.

But first, let’s consider some common approaches for dealing with three different  health issues:

1. Obesity/Diabetes. To lose weight, reducing diets are employed that create an energy deficit.  The most effective of these diets work by actively modulating the levels hormones such as insulin or leptin, by modifying the type of food we eat (low glycemic or low carbohydrate are best), or the size and timing of meals.  In the case of advanced diabetes (an insulin deficiency), exogenous insulin is administered periodically in a controlled manner. Alternately, diet pills or other appetite suppressants are used to moderate certain hormones and peptides involved in satiety.  The back-up strategy is to learn how to cope with always being somewhat hungry.
2. Addiction. Addictive cravings from cocaine, alcohol, or other substances or activities have been associated with overstimulated dopamine “reward” circuits.  Some  treatments involve the use of antidepressants to elevate baseline dopamine levels, The back-up strategy is to counsel abstinence to avoid triggering the dopamine circuits in the first place.
3. Depression. To counteract depression, antidepressant drugs (typically SSRIs) are prescribed to boost levels of neurotransmitters such as serotonin or dopamine. Or, we may try non-drug supplements or dietary options to increase the level of these neurotransmitters: for example, serotonin precursors such 5-HTP,  tryptophan-rich food such as turkey and carbohydrates such as potatoes, which allow dietary tryptophan to readily produce serotonin in the brain. The back-up strategy is psychotherapy to provide insight or coping skills to better deal with the underlying depression.

The organic imbalance model. These three seemingly different treatments share a common thread: they are all based on conceiving health problems as intrinsic organic imbalances in our metabolism or neurochemistry that you are either born with or develop early in life, and over which you have little control.   Once you accept this model, there are two basic strategies: an “active” strategy to rebalance internal biochemistry, usually by means of drugs, supplements, or diet. And a “passive” back-up strategy of accepting that you are biochemically different, and counseling ways to cope with these organic conditions as best youe can, while trying to minimize the risk of triggering flare-ups due to relapse, bingeing, or depressive episodes.

Signaling compounds. I’ll focus here more on the “active” interventions which involve trying to directly rebalance the levels of “biochemical messengers” or signaling compounds circulating in our bodies. I’m referring to hormones like insulin and leptin, glucagon, or adrenaline; or neurotransmitters like serotonin or dopamine, which are produced in response to external stimuli.  According to the imbalance model, the levels of these signaling compounds are out of balance: there is a surplus or deficiency of “communication” that needs to be adjusted. The resulting “message” conveyed by the signaling compound is “too loud” or “too soft” for normal bodily function.  So to correct this, a therapeutic intervention is devised which attempts to restore our health by adjusting the amount of the signalling compound in our system.  In effect, the treatment attempts to turn up or turn down the “volume” of the message by adjusting the amount of signaling compound, in order to re-normalize our response to external stimuli.

These active medical or dietary interventions should work, if the imbalance model is correct.  But in many cases the treatments backfire:  after perhaps seeing a short term benefit the effect dissipates, and in some cases symptoms actually worsen, or side effects develop.  After some initial weight loss, the weight is regained.  Attempts to overcome addiction frequently end with relapse and failure. And depression returns. The problem is that we are not mechanical machines, we’re adaptive organisms, regulated by homeostasis. Trying to control message intensity may work for a short time, but the body outsmarts us and compensates for the intervention. Our wonderful, adaptive bodies react to the increased level of signaling compounds by becoming less responsive to them, just as we learn to tune out a dog that constantly barks for attention.  When the message volume is turned up, the receiver volume is turned down.

Our efforts to change seem to be hampered by biological programs that resist these efforts at biochemical rebalancing. Some will explain this by arguing that’s because we are born with a biological set point that our body will “defend” or an addictive or depressive personality that we can’t shake.  Try as we might to fight this in the short term, it’s almost impossible to succeed in the long run.  A lucky few may prevail, but the vast majority are doomed to their biology destiny.

Even if you manage to normalize the level of signaling compounds, you are now stuck with another problem:  you are dependent on some drug, supplement, or special dietary restriction for the long term — maybe even for the rest of your life. Drug companies and dietary supplement suppliers are happy to provide you with a lifetime supply of these compounds for a price.  I don’t know about you, but I’d rather not be dependent long term on drugs or supplements, or even restrictive diets, if it doesn’t have to be that way.

There are grounds for pessimism here.  But there may be a better solution that gives us back control of our fate:  Receptor regulation.

Receptor regulation. Receptors are “message receivers” located throughout our bodies. They are typically transmembrane proteins located on the surfaces of cells, and they bind with hormones and neurotransmitters to “receive” the signal and initiate a sequence of changes in our bodies — often profound system-wide changes in energy utilization, tissue growth, or the perception of pleasure and pain. For some reason, receptors don’t get the public attention that gets showered on the communication chemicals — the hormones and neurotransmitters.  And yet, as I shall argue, the receptors may be far more important than the signaling compounds that they interact with, because they do not change by the minute or hour, but are long-lasting parts of the control systems of our bodies.  If hormones and neurotransmitters are the “software”, receptors are the “hardware”.

The key process to understand is called receptor regulation, the process which controls the number, location and sensitivity of receptors. There are two forms: upregulation (an increase in the number and/or sensitivity of receptors in each cell) and downregulation (the reverse process). Wikipedia explains downregulation by describing how insulin resistance develops in response to elevated insulin levels:

The process of downregulation occurs when there are elevated levels of the hormone insulin in the blood. When insulin binds to its receptors on the surface of a cell, the hormone receptor complex undergoes endocytosis and is subsequently attacked by intracellular lysosomal enzymes. The internalization of the insulin molecules provides a pathway for degradation of the hormone as well as for regulation of the number of sites that are available for binding on the cell’s surface without doubts. At high plasma concentrations, the number of surface receptors for insulin is gradually reduced by the accelerated rate of receptor internalization and degradation brought about by increased hormonal binding. The rate of synthesis of new receptors within the endoplasmic reticulum and their insertion in the plasma membrane do not keep pace with their rate of destruction. Over time, this self-induced loss of target cell receptors for insulin reduces the target cell’s sensitivity to the elevated hormone concentration. The process of decreasing the number of receptor sites is virtually the same for all hormones; it varies only in the receptor hormone complex. (Italics added by me for emphasis).

So not only are the insulin receptors drawn inside the cell (like a turtle into its shell); they are also actively digested and degraded, making them less available to readily redeploy when glucose and insulin levels drop again.  New receptors are always being synthesized, but they are degraded more quickly than they can be replenished if insulin levels remain high. The resulting downregulation of insulin receptors forms the basis for the condition of insulin resistance, in which insulin at normal levels loses its ability to efficiently shuttle glucose from the bloodstream into liver, muscle, brain, adipose or other tissues; the body responds by further increasing insulin, resulting in a vicious cycle of hyperinsulinemia. Reversing this process — growing new insulin receptors — takes time and requires sustained periods with low circulating levels of insulin in order to foster the growth of new receptors.

It is quite revealing to look at how how receptor regulation can undermine “message control” treatments,  due to the way the body adapts. Let’s take a look again at how this plays out in the above three examples of obesity, addiction, and depression:

1.  Obesity. Obesity is associated with high levels of two hormones: insulin and leptin. Normally, an increase in the level of either of these two hormones induces satiety upon reaching the hypothalamus in the brain. Leptin levels in the body increase with the amount of body fat, so leptin has been proposed as a physiological correlate for our “set point” weight: when body fat falls below a certain level, appetite induces us to eat more; when body fat increases, the associated rise in leptin levels leads to satiety. Insulin plays a similar but different role; it tends to regulate appetite on a shorter timescale than leptin, varying during each meal, and is more closely associated with visceral fat of the type more commonly found in men, whereas appetite regulation by leptin operates on more of a daily timescale and responds more closely to subcutaneous fat of the type more common in women. Insulin, of course, is directly involved with the storage and release of metabolic fuels. There are also many other regulatory hormones and sensory peptides, such as ghrelin, CCK and PYY, which adjust appetite based upon meal timing, gut sensations, and other inputs.  But insulin and leptin are key drivers of appetite.

The discovery of leptin, the “satiety hormone” by Jeff Friedman at Rockefeller University in 1993 provoked great excitement and expectations.  A well written account of this discovery is detailed in “Rethinking Thin“, the above-mentioned book by Gina Kolata. Studies in leptin-deficient ob mice and humans showed that individuals with defective production of leptin became ravenous and obese.  So the logical conclusion was leptin itself may be the magical “set point” compound that determines our weight.  Therefore, we should be able to provide leptin to the overweight to help them shed pounds. And in fact, adminstering leptin does work to counteract obesity in mice and humans that are genetically incapable of producing normal leptin, as Kolata describes poignantly in her chapter “The Girl Who Had No Leptin”.  It even works initially in normal or lean mice to reduce body fat. Amgen acquired the rights to leptin from Rockefeller University for $20 million plus royalties in anticipation of imminent commercialization. But after a long-term study in humans, the October 1999 issue of  JAMA reported disappointing results indicating very little weight loss, and even that in only in a small percentage of subjects. As Kolata observes:

The question, though, was, Why didn’t the obese people in Amgen’s study respond to leptin? The possibiity, or perhaps the likelihood, was that leptin was not their problem. These people were making plenty of leptin–they were not the human equivalent of the ob mice. And since adding more leptin did not make them lose weight, it must be that the hormone was being blocked from acting somewhere along its passage from the fat cells to the appetite-controlling pathways in the brain…Then [scientists] discovered that leptin can do something else. It can actually change the brain’s wiring diagram, strengthening circuits that inhibit eating and weakening the ones that spur the appetite. It can exert this effect at a critical period early in life, perhaps influencing appetite and obesity in adults.  And, in adulthood, leptin can again alter the brain’s wiring, permanently changing an animal’s appetite and weight. (RT, pp. 163-165).

The problem is often that excessive sustained levels of leptin, common in the overweight or obese,  can cause “leptin resistance” in which the leptin receptors are downregulated, so that they are fewer in number and become less sensitive to the leptin signal. As Byron Richards indicates in The Leptin Diet:

In overweight people, the communications involving insulin and leptin are inefficient. It is like making a phone call where no one answers. Insulin resistance and leptin resistance mean that the hormones don’t communicate efficiently in response to food. Thus a person has to overeat in order to get enough leptin into the brain to get a full signal. The pancreas may not hear the leptin signal to stop making insulin, which leads to excess insulin, fatigue, and possibly even more hunger within a few hours of eating…Several hours following the meal the extra insulin ends up taking too much sugar out of the blood, making a person hungry and tired-headed. (TLD, p 36)

With leptin resistance, adding more leptin no longer effectively inhibits appetite, because the brain and body have a reduced ability to respond to the extra leptin.  Conversely, lean individuals typically have more leptin receptors and greater leptin sensitivity, so their appetite is satisfied even at reduced leptin levels.  In short, the leptin system adapts so that the number of leptin receptors adjusts to the amount of leptin.

Interestingly, obesity is also associated with reduced number of receptors for dopamine, a neurotransmitter associated with pleasure or reward circuits in the brain. In 2001, Gene Jack Wang and Nora Volkow of the U.S. Department of Energy’s Brookhaven National Laboratory used Positron Emission Tomography (PET) brain scans to look at dopamine receptors in the brains of obese and normal individuals:

Obese individuals, the scientists found, had fewer dopamine receptors than normal-weight subjects. And within this obese group, the number of dopamine receptors decreased as the subjects’ body mass index, an indicator of obesity, increased.  That is, the more obese the individual, the lower the number of receptors.

A 2008 study of women and adolescent girls in New Zealand showed that this receptor deficit is at least partly genetic. The overweight females had the Taq1A1 gene that is associated with fewer dopamine receptors. This receptor deficit in the obese led them to overeat to achieve the level of pleasure or satiety that normal individuals reached with less food. This reduced level of dopamine receptors tends to make life a bit less pleasant for the obese when they are hungry and without food. Ingestion of food, particularly carbohydrates, temporarily raises the level of dopamine, eliminating the “pleasure deficit” and rewarding eating behavior.  Excessive eating or bingeing raises the dopamine levels even higher than normal, which can lead to a further downregulation of dopamine receptors, only worsening the craving problem. This effect is not only influenced by genes, but by diet; a 2010 study of rats fed a supermarket “junk food” diet showed raid desensitization of dopamine receptors a significant increase in appetite, and an unwillingness to return to eating “healthy” food.

The connection between obesity and the number and sensitivity of dopamine receptors is perhaps not so surprising, given how highly rewarding food can be for the obese; for many of the overweight, food becomes an addiction.  It is still quite striking that this translates to such a significant decline in the number of dopamine receptors, while the baseline level of dopamine actually increases.  Here, as with insulin and leptin, we have yet another example of reduced receptor levels being associated with obesity.  By analogy with insulin resistance and leptin resistance, we might say that the strong appetite of the obese is a direct result of “dopamine resistance”.

2. Addiction. What is particularly interesting is that these low levels of dopamine receptors are also characteristic of drug addicts and alcoholics.  Nora Volkow, one of the directors of the Brookhaven study, subsequently became director of NIDA, the National Institute of Drug Abuse. part of NIH, but her research on addiction actually predates the study she did on brain activity in the obese. She used PET brain scans to study dopamine receptors levels in alcoholics, cocaine addicts, and addicted smokers.  And, as you might guess, the same pattern of reduced levels of dopamine receptors was observed in addicts vs. non-addicted controls.  This is illustrated in the PET scan to the right, which shows dopamine binding activity for addicts (top row) vs. non-addicts (bottom row). Regions of greatest dopamine receptor activity are indicated with a color scale starting from red (most active), descending through yellow and green to blue and purple (least active).

The mechanism downregulation of dopamine receptors by cocaine has been elucidated:

Cocaine binds tightly at the dopamine transporter forming a complex that blocks the transporter’s function. The dopamine transporter can no longer perform its reuptake function, and thus dopamine accumulates in the synaptic cleft. This results in an enhanced and prolonged postsynaptic effect of dopaminergic signaling at dopamine receptors on the receiving neuron. Prolonged exposure to cocaine, as occurs with habitual use, leads to homeostatic dysregulation of normal (i.e. without cocaine) dopaminergic signaling via down-regulation of dopamine receptors and enhanced signal transduction. The decreased dopaminergic signaling after chronic cocaine use may contribute to depressive mood disorders and sensitize this important brain reward circuit to the reinforcing effects of cocaine (e.g. enhanced dopaminergic signalling only when cocaine is self-administered). This sensitization contributes to the intractable nature of addiction and relapse.

3.  Depression. A reduced number or sensitivity of neurotransmitter receptors has also been linked to mood disorders such as major depression. Depression has been associated with shortages of at least two neurotransmitters:  dopamine (which is associated with drive, motivation and pleasure), and serotinin (which is associated with a sense of well-being and pleasure).  While dopamine receptors are located largely in the brain, a little known fact is that only about 20% of serotonin receptors are in the brain, most of the other 80% are in the gut, blood platelets, and other organs.  That might help explain why serotonin is also associated with food and satiety.   Different types or depression are often associated with a different imbalance of neurotransmitters, so despite the prevalence of SSRIs, which are intended to restore serotonin levels, some forms of depression respond better to antidepressants which boost dopamine levels.

While antidepressants work for many people, a surprising number — some estimates put it at 50% or higher — are unresponsive. Furthermore, long term use of SSRI’s can have the effect of downregulating serotonin (5-HT2A) receptors with adverse results:

Another adaptive process provoked by SSRIs is the downregulation of postsynaptic serotonin 5-HT2A receptors. After the use of an SSRI, since there is more serotonin available, the response is to decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio. This downregulation of 5-HT2A occurs when the antidepressant effects of SSRIs become apparent. Also, deceased suicidal and otherwise depressed patients have had more [presynaptic] 5-HT2A receptors than normal patients. These considerations suggest that 5-HT2A overactivity is involved in the pathogenesis of depression

The last sentence in the above quote again points to the fact that a deficiency of post-synaptic serotonin receptors, in combination with  an excess of serotonin from diet, antidepressants, or elsewhere,  may play a role in both the genesis and worsening of depression.  The same phenomenon of receptor downregulation together with excess neurotransmitter has been noted with other antidepressants, such as MAO inhibitors and buproprion, that stimulate the production or prolong the lifetime of dopamine in the synapse.  This can lead to tolerance and withdrawal effects.

In short, in all these cases — obesity, addiction, and depression — receptors are becoming less sensitive to a signaling compound as a reaction to excessive levels of that compound.  So too much insulin and leptin lead to insulin and leptin resistance, too much dopamine to a downregulation of dopamine receptors.

………………………………….

HOW TO UPREGULATE YOUR RECEPTORS. So if directly changing the amount of signaling compounds is frequently frustrated by receptor downregulation, is there anything you can do to upregulate the receptors?  Fortunately, the answer is yes.  There are a number of measures that have proven particularly effective for deliberately increasing the number and sensitivity of key classes of receptors:

Step 1:  Strenuous exercise. Regular, intense exercise can upregulate your insulin receptors. In Dr. Bernstein’s Diet Solution, Richard Bernstein explains the role of exercise in actually reversing insulin resistance by growing new muscle tissue, and by increasing the density of glucose transporter receptors in muscle and other tissues.  While his advice is directed primarily towards diabetics, it applies more broadly to anyone with some degree of insulin resistance That includes most of us.  According to Dr. Bernstein:

The higher your ratio of abdominal fat to muscle mass, the more insulin-resistant you’re likely to be. As you increase your muscle mass, your insulin needs will be reduced…Long-term, regular strenuous exercise also reduces insulin resistance independently of its effect upon muscle mass…In my experience, it takes about two weeks of daily strenuous exercise to bring about a steady, increased level of insulin sensitivity…via increased production of glucose transporters in muscle cells. (DBDS, p. 170-1).

Furthermore, the exercise must be strenuous and “anaerobic” – not aerobic.  There are two reasons for this:

First, the blood sugar drop during and after continuous anaerobic exercise will be much greater than after a similar period of aerobic exercise. Second, to accomplish efficient transport of glucose into muscle cells, as muscle strength and bulk develop, glucose transporters in these cells will greatly increase in number. Glucose transporters also become more numerous in tissues other than muscle, including the liver.  (DBDS, p. 180)

Glucose transporter (GLUT4) receptors are upregulated by intense exercise.  A study reported in the New England Journal of Medicine showed that this upregulation begins to happen within hours, but significant and sustained improvement requires repeated exercise sessions over several weeks.  When insulin levels are kept low, the glucose transporters migrate from a location inside the cell to protrude beyond the cell surface, becoming more available to bind glucose and shepherd it into the interior of the cell.  With time, the cells can actally express or “grow” additional receptors, increasing the overall rate of glucose transport.  This increased response rate is synonymous with “insulin sensitivity”.

The benefits of anerobic exercise extend not only to upgregulation of insulin receptors, but also to maintaining high levels of dopamine “reward” receptors. A study of exercised rates by McRae et al at University of Texas showed that regular exercise has a protective effect on D2 dopamine receptors, while keeping levels of dopamine (DA) and dopamine metabolite (DOPAC) low.  Unexercised rats saw both a decrease in D2 receptor density and an increase in circulating dopamine.

Step 2:  Calorie restriction and intermittent fasting. Another brain scan study at Brookhaven National Laboratory showed that restricted eating led to higher numbers of dopamine receptors in obese rats:

The scientists found that genetically obese rats had lower levels of dopamine D2 receptors than lean rats. They also demonstrated that restricting food intake can significantly increase the number of D2 receptors, partially attenuating a normal decline associated with aging.

This research corroborates brain-imaging studies conducted at Brookhaven that found decreased levels of dopamine D2 receptors in obese people compared with normal-weight people,” said Brookhaven neuroscientist Panayotis (Peter) Thanos, lead author of the current study, which will be published online in the journal Synapse on Thursday, October 25, 2007.

One of the essential points to understand here is that if calorie restriction and intermittent fasting are effective, it is not for the reason that most people think explains this (that you are creating a calorie deficit).  Rather, intense exercise and fasting work because they resensitize and grow your insulin and dopamine receptors in a way that allows you to get enough energy and pleasure from eating less food.   This means that not only are the receptors upregulated, but you also get the energy and pleasure when you need it.  So restricting calories is not good enough.  You must eat foods that maximize insulin senstivity (e.g. containing adequate essential fatty acids, protein, magnesium, etc.) and foods which give you enough pleasure so as to satisfy your “pleasure budget”, but not so much as to downregulate your dopamine receptors.  My experience is that intermittent fasting, using a varied diet, is the best way to do this.  One reason that pure “starvation diets” like that used in the Minnesota Starvation Experiment may have failed is that the diet failed to supply adequate nutrients that to support receptor function for cellular energy and pleasure.  (The 1560 calorie/day regimen consisted only of potatoes,  rutabagas,  turnips,  bread and macaroni — so go figure!)

A particularly effective protocol for improving insulin sensitivity and upregulating glucose transporter receptors is called “fasted workouts”: a combination of intense exercise and intermittent fasting, in which eating is postponed until after one works out.  One of the foremost practioners of this approach is Martin Berkhan, who I’ve referenced on the Fitness page of this blog, and whose Leangains blog I’ve listed under the Diet links.  Martin summarizes the research by DeBock et al. and Cluberton et al. that documents the physiological beneifts of fasted workouts, including enhanced insulin sensitivity based upon a six-week study with four 60-90 minute workouts per week. The study controlled for dietary intake, and compared results of those who fasted (F) with the control group (C) that ate prior to working out. Among other variables, the study compared changes in the levels of the GLUT4 transporter, a type of insulin receptor in the muscles, between the F and C groups:

Glucose transporter type 4 is a protein responsible for insulin-regulated glucose transport into the muscle cell. It increased by a whopping 28% in F but only 2-3% in C (not mentioned in the paper but this is my estimate based on the graphs). This partly explains why F saw superior results in regards to glucose tolerance and insulin sensitivity. Since GLUT4 is triggered by AMPK, which is increased when glucose availability is low, i.e. during fasted training, one would assume the GLUT4 increase could then be explained by an increase in AMPK. This was found to be true: AMPK increased by 25% in F, which correlated closely with the increase in GLUT4 content.

Step 3: Deconditioning and extinction. Pleasure reward circuits do not change overnight.  But the good news is that there is plenty of evidence that these reward circuits can be extinguished by classical conditioning techniques.  I’ve discussed these deconditioning techniques in depth on the Psychology and Diet pages of this blog, and I’d recommend looking there for details.  Extinction involves merely refraining from the undesired behavior (eating, addictive drugs) and allowing the cravings to happen without reinforcing them.  It may surprise you how quickly your reward circuits recover, and it is very likely that this involves upregulation of dopamine receptors, so that the brain is more easily “satisifed” without the previously craved behavior. Deconditioning is more active than extinction; it requires actively exposing yourself to cues which normally set off the addictive response.  This may sound extremely difficult, but is attested to by extensive research, as well as the personal experience of several people who have posted here on the Forum, including myself.   One of the more successful appliations of active deconditioning is the Sinclair Method, which has been used successfully to extinguish alcoholism while training the former alcoholic to drink moderately. The key is the use of a dopamine blocker, naltrexone, to block the reward circuits during exposure.

Any type of extinction should benefit from simultaneous reinforcement of healthy alternative sources of pleasure, while engaging in exercise and intermittent fasting to rebuild the density and sensitivity of receptors.  Unless you increase your level of dopamine receptors, you’ll always be vulnerable to the temptation of any pleasure that can “fill your pleasure deficit”.

………………………………………

THE RECEPTOR CONTROL THEORY. Based upon a synthesis of extensive evidence, I’m putting forward in this post an alternative to the classic set point theory of Gordon Kennedy:  the receptor control theory.  This is a general hypothesis of biological regulation which applies to more than just weight control; it applies to any homeostatic variable that is controlled by cellular receptors — even, for example, pleasure and motivation. Whereas the classic set point theory of body weight posits a fixed genetic set point for each individual,

the receptor control theory postulates that our set points for regulating weight, energy, or pleasure are variable; they are directly related to the number, sensitivity and location of cellular receptors in our bodies, and can be modified by changing the number and sensitivity of these receptors.

For example, the set point for your body fat is controlled by insulin and leptin sensitivity, which is determined by the number and functional sensitivity of insulin and leptin receptors throughout your body.  As the number and sensitivity of insulin and leptin receptors decreases, body weight set point goes up. But unlike the set point theory, body fat set point can also go down by increasing the number and sensitivity of these receptors — for example by the use of strenuous exercise, intermittent fasting, and extinction.

If you don’t change the number and sensitivity of your receptors, your set point will not change.  Under these circumstances, the receptor control theory agrees with the classic fixed set point theory. However, the receptor control theory provides a way to change your set point by upregulating your receptors.

The pleasure budget. The receptor control theory goes beyond weight management to explain more generally the regulation of pleasure in your life.  If you have ample dopamine receptors, then a wide variety of stimuli– including food, social interactions, work, and other interests– should provide you with sufficient pleasure to make life not just bearable, but interesting.  However, if you end up with an undersupply of dopamine receptors — whether it be from birth, addictions or unremitting stress — then your baseline pleasure “set point” will be low and you’ll be vulnerable to depression, low self-esteem and other aspects of unhappiness. Addictive escapes may provide temporary (but unsustainable) bursts of dopamine, serotonin, and other feel-good neurotransmitters, but at the cost of further downregulating dopamine receptors and feeling worse later on.

It may be the case that all of us have a certain “pleasure budget” — perhaps we need a certain amount of pleasure every week, and we’ll find a way to get it, one way or another.  One of the commenters (zdd) to my earlier post on The opponent-process theory of emotion expressed this point well, when speculating about why diets like Shangri-La and Atkins work so well initially, but eventually become less effective:

If there is a set point, I believe it’s not a weight set point but rather a pleasure set point. When you don’t reach the set point, cravings start and when you go over the set point (staying too long at the fair) you get feelings of aversion.

I doubt if the pleasure set point changes very much. People simply switch sources of pleasure. Stop smoking, and you start eating more. Much of the pleasure of being on this diet comes from the pleasure of feeling in control. Once the novelty of control wears off people will have to look for other sources of pleasure or they will go back to getting pleasure from food.

I think this insightful comments carries a useful warning: that behavioral changes such as diets which cut off one source of pleasure may require us to find a way to replace that source of pleasure, or else risk rebounding from the diet and regaining the weight we lost.

The good news here is that there are proven ways to raise our “pleasure” set point.  The bad news is that they require significant and sustained effort – no quick fixes.  And yet it is the most sustainable way to increase pleasure in life.  To paraphrase a saying about fishing sometimes attributed to the Bible: “Give someone a neurotransmitter and they’ll feel good for an hour; teach someone to grow more receptors and they’ll feel good all the time.”

Explanations. The receptor control theory explains a number of observations that cannot be accounted for by classical set point theory:

1. Biology is not destiny. Individuals do differ genetically in their tendency to gain weight or to be prone to addiction or depression.  You are born with a certain density of receptors and this can be influenced further during prenatal and postnatal development.  But it is not the end of the story. The types of foods you eat and the frequency of eating have strong effects on insulin and leptin sensitivity.  Likewise, exercise, hard work and a stoic practices can sensitize your dopamine receptors and make you happier and less prone to depression.
2. Obesity is not a constant. Both the weight gain of individuals as they age, and the obesity epidemic of recent decades are often blamed on “calorie imbalance”: eating too much and exercising too little. But this doesn’t explain why this caloric imbalance is happening now as opposed to earlier. Sometimes the uptick in obesity is blamed on the increasing availability of tasty high-calorie food and a less active lifestyle. But that explanation cannot be right, because there has always been tasty food. And as Kolata has shown, controlled interventions to reduce calories and enforce more activity have a poor track record.  The reason that body weight set points are rising has more to do with changes in the amounts of food and exercise, as it does with specific types of food, eating patterns and exercise–and the long term hormonal influences of these changes on receptor sensitivity.
3. Permanent weight loss is still possible. Granted, most diets don’t work. Quick weight loss diets don’t work because they don’t allow a biologically realistic amount of time for receptors to upregulate; receptor upregulation is a gradual process that requires persistence and effort. Certain diets are quite effective in the short term, including low carbohydrate diets, low glycemic diets, and the Shangri-La Diet (which temporarily suppresses appetite). These diets will temporarily change levels of hormones, neurotransmitters and other signalling compounds to induce satiety and weight loss. However, unless appetite circuits are permanently “re-wired” by upregulating hormonal and neural receptors, weight loss will be temporary.  Appetite will remain vulnerable to coming back like a tiger, and you may return to your old set point weight — perhaps even plus a few pounds.  The best way to upregulate metabolic and appetite receptors is by strenuous exercise, intermittent fasting or deconditioning.  Given enough time, persistent and habitual dietary changes can lead to permanent weight loss, particularly when combined with reduced eating frequency, intense exercise, and deconditioning.

Biological basis for Hormetism. The receptor control theory also provides us with a some biological underpinnings for Hormetism and Stoicism, as advocated in this blog. Hard work –tough, uncomfortable and challenging activities–can lower our metabolic and pleasure set points, helping us to lose weight and making us less vulnerable to addictions, cravings and depression.  What is exciting to me is that this theory may provide a possible biological basis for the psychological Opponent-Process Theory of Richard Solomon.  The basis is located not in transient chemical messengers like neurotransmitter and hormones, but rather in the adpatable receptors located throughout our body on every cell.  These receptors are part of the hardware or firmware of our bodies and brains.   Receptors are a part of us that cannot be changed overnight, but can only be changed with persistent effort.  (And they will not disappear so readily either).

I will be the first to acknowledge that at this point the receptor control theory is just that — a theory.  It has support by scientific evidence, but many questions remain.  And yet it is a productive theory which generates many testable hypotheses.  It provides us with a possible basis for understanding the benefits of less-studied hormetic or Stoic practices such as showering or swimming in cold water, radiation hormesis, or allergen immunotherapy.  Do these types of stress also result in upregulation or downregulation of specific cellular receptors involved in pain perception, cellular repair, inflammation or immune response? Can we measure and better understand these responses at the level of receptors? Are there practical ways to measure the number and sensitivity of our receptors, so that we can track progress? Receptor change is probably only one of many mechanisms that explain hormesis, but it may be an important and underappreciated one.  These questions make good topics for future posts.

Finally, unlike the classic set point theory, the receptor control theory is not fatalistic, but is optimistic:  By combining insights as old as ancient Stoic philosophy with a contemporary scientific understanding of psychological conditioning and the plasticity of cellular signal receptors and receptor circuits, we can work to achieve fitness and weight loss, freedom from addictive compulsions, and chart other major changes in our metabolic and psychological well being.

—————————————————————————————————————————————————

Consider the following ten situations:

1. Drug addicts, before becoming addicted, experience the euphoria of a drug with few negative consequences. Over time, however, they develop a tolerance for the drug, requiring increasing doses to get the same high.  At the same time, their cravings and distressful feelings increase when going without the drug, leading to increased in withdrawal symptoms and a cycle of increasing drug use.
2. Firefighters and emergency room doctors have stressful jobs, but many find themselves experiencing an irresistible rush and heart-throbbing exhilaration from these fast-paced occupations.
3. New lovers, after a honeymoon period of initial infatuation, often experience a drop-off in affection, leading to dissatisfaction, fights, and sometimes breakups.  When reconciling after the breakup, they experience renewed closeness for a period of time. Typically, the more intense the infatuation, the greater the strife and negativity during the falling out periods.
4. Marathoners and other runners often experience a “runner’s high” which builds up during longer, more strenuous runs, and can extend for hours or even days after a run. Runner’s high has been associated with release of endorphins, a natural “opiate” produced by the body.
5. Infants who are given a bottle and start sucking on it experience pleasure.  But if the bottles are removed before the infants have finished feeding, they universally cry.  And yet they would not have cried if the bottle had never been given.
6. Depressed adolescents often resort to “cutting”, a form of self-mutilation that introduces some pleasure or even a high into their otherwise sad or pleasureless day.  They often find the need to increase the cutting to maintain the pleasure.
7. Scratching an itch generally relieves the itch and can be pleasurable, but often this ends up making the itch more intense and, after repeated itching, even painful.
8. Horror movies, which initially are disturbing or even terrifying, can become addictive
9. Politicians and executives in positions of power come to crave the power.  When they are out of the limelight, they experience a letdown, boredom, or even depression.  Upon retirement, this depression can lead to poor health or shortened longevity.
10. People who donate blood frequently report a sense of well being and pleasure that cannot be explained in terms of the blood removal itself.

Can you see the pattern?  In the odd-numbered examples above, pleasure turns to pain; in the even numbered examples, pain becomes pleasure. And in all cases, the effect intensifies with repetition. But why does this occur?  One possible explanation for these types of situation is described in William Irvine in his book “A Guide to the Good Life”:

The psychologists Shane Frederick and George Loewenstein have studied this phenomenon and given it a name: hedonic adaptation. To illustrate the adaptation process, they point to studies of lottery winners. Winning a lottery ticket typically allows someone to live the life of his dreams. It turns out, though, that after an initial period of exhilaration, lottery winners end up about as happy as they previously were. They start taking their new Ferrari and mansion for granted, the way they previously took their rusted-out pickup and cramped apartment for granted. (Irvine, p. 66).

Hedonic adaptation is the experience of “getting used to” a good or pleasurable thing until one returns to a state of relative indifference or equilibrium, feeling about the same as one did beforehand. As I describe in more detail on the Stoicism page of this blog, Irvine goes on to point out how the Greek and Roman Stoics were able to combat hedonic adaptation by practicing techniques such as “negative visualization”, in which they regularly took time to vividly imagine loss of people, relationships and possessions they held dear, so they could better appreciate what they had.

Hedonic reversal and habituation. While hedonic adaptation of this sort certainly exists, the ten situations I listed above are quite different than than that of the lottery winner that Irvine describes. My ten situations do not involve a return to homeostasis or equilibrium. They involve a total switch, what I will call hedonic reversal. Pleasure becomes pain; pain turns to pleasure. This is the phenomenon that Richard Solomon tries to explain in his paper.  Solomon quotes Plato, who may been the first to describe true hedonic reversal and puzzle over it:

How strange would appear to be this thing that men call pleasure! And how curiously it is related to what is thought to be its opposite, pain! The two will never be found together in a man, and yet if you seek the one and obtain it, you are almost bound always to get the other as well, just as though they were both attached to one and the same head….Wherever the one is found, the other follows up behind. So, in my case, since I had pain in my leg as a result of the fetters, pleasure seems to have come to follow it up.

In hedonic reversal, a stimulus that initially causes a pleasant or unpleasant response does not just dissipate or fade away, as Irvine describes, but rather the initial feeling leads to an opposite secondary emotion or sensation. Remarkably, the secondary reaction is often deeper or longer lasting than the initial reaction.  And what is more, when the stimulus is repeated many times, the initial response becomes weaker and the secondary response becomes stronger and lasts longer. This is what happens quite clearly in the case of addiction. After repeated administration, the original dose no longer gives the same high, so it must be increased to achieve that effect. In addition, as time goes on, abstaining from the addictive dose becomes more difficult, while cravings, anxiety and depressive feelings increase. The mirror image of this addictive pattern is apparent in the case of endorphin-producing athletic activities like running, or thrill-seeking pasttimes like parachuting. Solomon reports on a study of the emotional reactions of military parachutists:

During the first free-fall, before the parachute opens, military parachutists may experience terror: They may yell, pupils dilated, eyes bulging, bodies curled forward and stiff, heart racing and breathing irregular. After they land safely, they may walk around with a stunned and stony-faced expression for a few minutes, and then they usually smile, chatter, and gesticulate, being very socially active and appearing to be elated….The after-reaction appears to last about 10 minutes…After many parachute jumps, the signs of affective habituation are clear, and the fearful reaction is usually undetectable. Instead, the parachutists look tense, eager or excited, and during the free-fall they experience a “thrill”. After a safe landing, there is evidence of a withdrawal syndrome. The activity level is very high, with leaping, shouting…and general euphoria. This period, often described as exhilaration, decreases slowly in time, but often lasts for 2-3 hours. Indeed, I was once told by a sport parachutist…that his “high” lasted 8 hours. A new, positive source of reinforcement is now available, one that could never have eventuated without repeated self-exposures to an initially frightening situation to which the subject then becomes accustomed. (Solomon, pp. 693-8)

Thus, both the addictive pattern and the thrill pattern share the features of hedonic habituation (reduced intensity of the primary response) and hedonic withdrawal (heightened intensity of the secondary, opposite response). In surveying and studying a wide range of such experiences, Solomon found a common pattern of hedonic contrast, which he represented as follows:

baseline state → State A → State B

State A is the initial emotional or “affective” response to a stimulus, which can be either pleasant or unpleasant.  Typically, the first time a novel stimulus is applied, the primary or State A response is most pronounced at the outset and then tapers to steady level as long as the stimulus is maintained, as shown below in Figure 4.  For example, exposure to the heat of a sauna or hot tub may cause an initially hot or burning sensation, which diminishes somewhat over time. Once the stimulus is removed, the sensation is replaced by a contrasting sensation or affective state, the after-reaction, or State B.  State B is opposite in hedonic character to State A. If one is pleasant, the other is unpleasant, and vice versa. Initially, and after the first few stimulations, State B typically has a much lower intensity than State A, but often lasts longer in duration, before it eventually decays and returns to the baseline state.

What Solomon noticed is that after many repeated stimulations, the intensity of State A typically diminishes, both in peak intensity and steady state intensity. This is the hedonic habituation effect, also called “tolerance”, and it is seen with both pleasant and unpleasant affective reactions. The only way to increase the intensity of State A is to increase the magnitude of the stimulus. At the same time, with repeated exposures, the secondary affective State B often intensifies and lasts longer. This is the hedonic withdrawal effect. This combination of habituation and withdrawal effects is shown in Figure 5:  For addictions, the pleasurability of the stimulus diminishes with time and the unpleasant withdrawal grows in both intensity and duration. For the thrill-seeking or excitatory pattern, the stressfulness or unpleasantness of the stimulus is reduced with repetition, while the  ”withdrawal” becomes more pleasant and lasts longer, before returning to baseline.

—————————————————————————————————————————————————-

The opponent-process theory. So far, all we have presented is a qualitative description of some common patterns of sensory or emotional response, without any real explanation for why these patterns occur as they do. But Solomon’s real innovation is that he can explain these patterns by decomposing them into more elemental underlying biological processes. His central insight is that the nervous system is organized in such a way that any sensory or emotional response can be decomposed into two concurrent processes. The State A response diagrammed in Figures 4 and 5 above is in reality a composite of two complementary physiological processes:

• a primary process “a”, which is the direct observable response to the stimulus; and
• an opponent process “b”, which acts to inhibit or counteract the primary process.  It occurs at the same time as the primary process, but is not always evident or easy to perceive.

To understand how these processes actually work in practice, let’s look more closely at Figure 7 below. The opponent process “b” actually begins shortly after the initiation of the primary process “a” and acts to dampen it during what we observe as State A. Because “b” is both smaller and opposite in effect to “a”, it acts to reduce the net impact of “a”.  That explains why the intensity of the A process is greatest at the outset, but drops as the stimulus in continued.   According to Solomon, for a novel stimulus the “b” process is smaller and more sluggish than the “a” process.  It is slower to built to its steady state level (asymptote) and slower to decay after the stimulus stops.  This is shown in Panel A of Figure 7:

So what happens to bring about habituation after many repetitions of the stimulus, when the stimulus is no longer novel? According to Solomon, the primary “a” process remains unchanged in response to the stimulus.  What changes with repetition is the opponent process “b”.  As depicted in Panel B of Figure 7, after many stimulations:

• it intensifies
• it starts earlier (reduced latency period)
• it decays more slowly

The net impact of these changes in the opponent process is to progressively dampen the magnitude of State A and increase the speed, magnitude and duration of State B.  Thus, without any changes in the primary process, these changes in the opponent process can fully explain the increase in both tolerance and withdrawal, as shown in Figure 7.

Biological basis. Opponent processes are not just some clever hypothetical construct that Solomon came up with out of thin air. These kinds of inhibitory processes are common in biological systems.  For example, many or perhaps most neurotransmitters, hormones, and biological receptors have corresponding opposites, which act to inhibit or moderate the primary response. These inhibitory processes serve a useful biological control functions by preventing over-reactions to environmental disturbances. They form the the biological basis of systems of homeostasis, systems that enable organisms to resist or adapt to disturbances to their steady functioning.

Solomon’s opponent-process theory also identifies several key factors that can strengthen or weaken the opponent “b” process.  His paper summarizes some very clever animal research on distress behavior in ducklings, from which he deduced that the opponent process can be strengthened in three primary ways:

• increasing the intensity of the initial stimulus exposure
• increasing the duration of the stimulus
• shortening the interstimulus interval (the time between stimulus exposures)

Interestingly, merely repeating the stimulus, in and of itself, had no effect on strengthening of the opponent process if the stimulus was too weak or too short, or if the interstimulus interval was too long.  In particular, he found that, depending on the inherent duration of the opponent process, the interstimulus interval had a major effect on whether or not the opponent process will increase in strength.  According to Solomon

The critical decay duration is that disuse time just adequate to allow the weakening of the opponent process to its original, innate reaction level. If reinforcing stimuli are presented at interstimulus intervals greater than the decay duration, then the opponent process will fail to grow. (Solomon, p. 703)

Each opponent process has an inherent decay behavior, that is, a rate at which it fades away.  This will depend on the specific physiological and biological underpinnings of that process.  On a biochemical level, for example, this decay duration may depend on the half-life of the neurotransmitters, hormones, or receptor behavior involved.  It will surely also involve higher order processes which relate to the nervous system and psychological conditioning of the individual.  Figuring out the decay duration of various opponent processes should be a matter open to empirical determination.  It can be approached both by psychological investigations on others (or on oneself), and also by looking into the underlying physiological and biochemical mechanisms.

The final element of Solomon’s theory is a phenomenon he calls “savings”.  Although opponent processes can be weakened or faded away by avoiding the stimulus for an extended period of time, that does not mean they leave no memory traces. Studies show that these opponent processes are more quickly reactivated the next time they are re-stimulated. Reflexes and emotional reactions build up more quickly when reactivated than they did with the initial stimulation. According to Solomon,

Such a phenomenon is not unexpected. In alcohol addiction, for example, the abstainer is warned that one drink may be disastrous, and the reason is the savings principle. The reexercise of alcohol’s opponent-process system strengthens the withdrawal syndrome very rapidly and sets up the special conditions for resumption of the addictive cycle. Cigarette smokers report the same phenomenon: Readdiction to nicotine takes place much more rapidly than does the initial addiction. (Solomon, p. 703)

This savings effect also applies to positive opponent effects, such as the exhilaration experienced by skydivers or runners when resuming their thrilling or strenuous activities after a hiatus.  Understanding this effect is important in designing strategies for avoiding or minimizing the negative effects of relapse, as will be discussed below.

Put into simplest terms, the opponent-process theory explains the psychology of addiction and thrill-seeking in terms of the strengthening of inhibitory processes.  These inhibitory processes  get stronger when stimulation of a primary emotional response is sufficiently intense, sustained and frequent.  They become evident only when there stimulus and the primary processes are not present, and typically last for some time afterwards.   On subsequent re-exposure the stimulus, opponent processes often reactivated more quickly.

Is this a biologically realistic explanation?  Perhaps Solomon has not generated a broad enough set of hard physiological data to conclusively prove his hypothesis.  However, there is still a strong case in favor of it. First, his hypothesis provides a model which offers a coherent and consistent explanation for a wide range of  sensory and emotional behaviors for which there are few other good explanations. Second, there one application of the Opponent-Process theory–to an area unrelated to emotions–which has already been empirically verified:  the explanation of color perception. It is worth spending a paragraph on this because it provides some insights into the biological reality of this theory.

The opponent-process theory of color vision. Until the late nineteenth century, the primary theory of color vision was the trichromatic theory, which held that color perception was the result of the stimulation of three different types of cone receptors in the retina of the eye.  In 1892, Ewald Hering first proposed the opponent-process theory of color vision. He observed that any color can be uniquely analyzed in terms of the colors red, yellow, green, and blue, and noted that these four primary colors exist as the complementary pairs red-green and yellow-blue. Hering’s theory accounts for how the brain receives signals from different kinds of cone cells and processes and combines these signals in real time. The opponent-process theory of color vision received further support in 1957 in studies by Hurvich and Jameson, and in 2006 by Liapidevskii. Some of the most compelling evidence for the theory is the phenomenon of complementary color after-images, which cannot be explained by the tricolor theory.  You can demonstrate this for yourself by staring at the red dot in the middle of the image below for 30 seconds without letting your eyes drift from the center; then look at a blank white sheet and you will see the image with a more familiar set of colors. (It may take a while for the image to develop).

Looking at the colors under bright light and for longer periods enhances the opponent (inhibitory) processes in the receptors, which intensifies the after-images, just as one would predict based on the principles Solomon found for sensation and emotion.

Consider the similarity between this contrasting after-image response to visual stimuli and the emotional or affective responses that that Solomon found in his animal studies.  The sensory after-images may be less intense and of shorter duration, but the principle is the same, and both phenomena illustrate how opponent processes can arise within our nervous systems. Beyond the processing of simple nerve signals, such as those involved in visual sensory perception, the opponent process theory can account for psychological processes of increasing complexity and at multiple levels, based on the well established fact that the brain is able to integrate sensory information by adding and subtracting different excitatory and inhibitory inputs from different receptors and neurotransmitters.

Practical applications.  Besides explaining common sensory and emotional reactions, I believe the opponent-process provides some very practical guidance for how we can use pleasant and unpleasant experiences to our advantage.  This guidance can be boiled down to seven basic insights:

1. Be aware of hidden processes! The most important insight is to be aware that any primary sensory or emotional stimulus, whether pleasurable or unpleasant, will give rise to opponent processes of an contrasting nature.  Even though you most likely cannot directly perceive them, these opponent processes are happening–and even growing in strength–at the very same time as the primary emotions and sensations that you do perceive.  When the primary emotions and sensations stop or pause, these contrasting processes emerge into consciousness!  For example if you put your hand in cold water, a “warm” opponent processes is being stimulated, but you feel that warmth only once you withdraw your hand from the water. And the pleasure of overindulging in sweet desserts is likely to be followed by an unpleasant reaction that arises some time after you stop eating.
2. Avoid overexposure to pleasurable stimuli. This does not mean that you should minimize or avoid direct pleasure! Just be aware that too much of a good thing too often can backfire — and be aware WHY that is so. By remaining vigilant, you need only to moderate the intensity and frequency of pleasant stimuli to ensure that the opponent processes do not build up. For example, eating small portions of delicious foods, and spacing out meals — or even individual bites — will tend to reduce the level the opponent processes (cravings) that would otherwise reinforce appetite and cravings. When you go for that second cup of coffee, you may marginally increase your alertness in the short term, but realize that you are at the same time continuing to stimulate a reactive opponent process, counteracting the caffeine high, that may lead to increased tiredness later on.  There is a biological argument for moderation!
3. Use unpleasant and stressful stimuli to indirectly build pleasure. This is one of the most powerful insights of the opponent-process theory. By judiciously exposing ourselves to intermittent stresses, of sufficient intensity and frequency, we activate in our bodies and psyches some powerful opponent processes, which in turn result in heightened pleasure and satisfaction. Depending on the type of stimulus, these indirect pleasures can be short-lived or more sustained. Stressful or unpleasant stimuli can therefore be thought of as a form of “psychological hormesis”:  The nervous systems is activating certain pleasurable inhibitory processes in order to defend against and build tolerance to stress. These pleasure-generating defense mechanisms are real, biological processes which operate in our nervous systems. One well known example is the production of endorphins, our natural opiates, which can be produced by engaging in strenuous exercise. Endorphins literally help us to endure the pain of exercise by providing a counteracting pleasure. So by increasing the intensity and frequency of stress exposures, we are not just building tolerance–we are actively building up a sustained background “tone” of pleasurable emotions. This is very much in line with what the Stoics called “tranquility”. As explained on the Stoicism page, Stoic tranquility is not apathy or a lack of feeling!  On the contrary, it is a positive sense of equanimity, contentment, and happiness that endures and supports us.  It is the opposite of depression; you might even call it “elevation”.
4. Indirect pleasure is superior to direct pleasure. So we have learned that we can paradoxically use pain or discomfort to indirectly cause pleasure.  But is there any reason to think that the pleasure resulting from running, hard work, cold showers, or skydiving is superior to the pleasure from sweet desserts or scratching an itch? Aren’t they equivalent? Doesn’t any pleasure, whether direct or indirect, nevertheless have the potential to lead to addiction?  This is an interesting question, but I think the opponent-process theory makes the case that indirect pleasures — those that results as reactions to stress — are superior. There are two main reasons for this:  First, according to Solomon, opponent-processes are “sluggish”; they take time to build, and decay more slowly. They continue even when the stimulus stops. And unlike direct pleasures, which may be more intense, there is no sudden withdrawal reaction when they stop, hence no “craving”. They tend to fade slowly. Second, the initial unpleasant stimulus — exercise, work, cold sensations — must be sufficiently unpleasant to be effective. This initial unpleasantness will always be a “barrier” that requires conscious effort to face and overcome. If it starts to become “addictive”, it is easier to let this unpleasant barrier stand in the way. It is easy to decide not to go running or take a cold shower if one becomes concerned it is becoming too habit-forming or detrimental to one’s health.
5. Use unpleasant stimuli to counteract addictive pleasures. This is one of the most interesting, and I think unexplored, applications of the opponent-process theory. Addictions are characterized by increased cravings. These arise when opponent process build up in reaction to pleasurable primary stimuli that are too intense and frequent. The craving can become a sustained background “tone” that is always there when the pleasurable stimulus is absent. And the “savings” effect makes the opponent cravings come back more easily. But we can overpower these cravings by deliberately introducing unpleasant stimuli at the same time as the addictive cravings, in order to generate new pleasurable opponent processes. The key is to time the unpleasant stimuli to coincide with cravings or withdrawal, and make them sufficiently intense and frequent, that one builds up sufficient background pleasure tone to counteract the unpleasant anxiety that typically accompanies addictions. So fight cravings by adding a new stressful activity like high intensity exercise, cold showers, or intermittent fasting! It may also help explain why cue exposure therapy — exposing oneself to the forbidden fruit without partaking — can often be more effective in extinguishing addictions than merely abstaining or avoiding the addictive stimulus. It is possible that active cue exposure might generate a type of acute “stress” that “burns out “the original craving with an opposing pleasure. This is like fighting fire with fire!
6. Don’t abuse pain and stress. Despite the potential benefits of controlled stress and unpleasant stimuli to indirectly induce sustained pleasure or “elevation”, this approach is easy to misinterpret or apply incorrectly. Some might take this to be a justification for masochism or self-harm, but it is not. The key here is to carefully think through the consequences of one’s actions. Does the application of the stress or unpleasantness result in an objective strengthening of your body and mind — or does it lead to physical or psychological harm?  Depressed teens sometimes engage in a practice called “cutting” to relieve their depression and apathy, because it can actually reactivate pleasure or a rush that fills a gap and can become addictive. Most likely, this pleasure can be explained in terms of opponent processes that release some of the same endorphins or other neurotransmitters as exercise does. But one needs to distinguish between objectively harmful activities like cutting and beneficial habits like exercise or cold showers. Far from injuring oneself, these beneficial uses of stress and “pain” act to act to build strength, resilience, and long-term happiness.
7. Optimize your stimulation schedule. Be aware of critical decay durations and savings effects of opponent processes, for both pleasant and unpleasant stimuli. Addictions and cravings can be minimized by reducing the frequency of exposure to pleasure-triggers to allow enough time for any cravings to decay. The next time you are mindlessly wolfing down bite after bite of an addictive snack like popcorn or candy, try spacing out bites to allow the craving sensations to die off between bites and see whether you end up satisfied with fewer bites. On the flip side, if you are finding it hard to get started on a healthy habit like strenuous exercise, cold showers, or fasting, it may be that you need to increase the frequency and intensity of the new habit until it takes. According to Solomon, it will become increasingly pleasant if you do this.

Since becoming aware of the opponent-process theory, I applied it to myself in two instances recently:

• On the pleasure side, I reduced my craving for alcohol by drinking less frequently, and limiting the amount that I drink.   The pleasure remains, but the daily cravings have disappeared. I’ve documented this on the Discussion Forum of this blog.
• On the pain side, I have increased my enjoyment of cold showers by never missing a day, by lengthening the showers, and by making sure to expose my most sensitive body parts to the coldness.  This has significantly increased the pleasure I feel, and it comes on more quickly while in the shower (within 10-15 seconds, versus previously more than a minute) and the warm, exhilarating post-shower feeling lasts all morning.  I’m happy all the time, and I definitely feel less stress.

Think about how this might apply to your own situation. Are there pleasures in your life that tend to result in cravings when they are absent? Can you think of ways to introduce healthful but somewhat unpleasant stress into your life in a way that builds your resilience and at the same time a deeper level of satisfaction and sustained pleasure?  Can you use this indirect pleasure to displace cravings or dissatisfaction? And in both cases, how aware are you of the relationship between the intensity and frequency of the stimuli, and the tendency to foster opposing processes that turn pleasures into pains, and pains into pleasures?

The potential applications are infinite!

Models of addiction. There are a number of different views of what addiction is. The medical model views addiction as a disease, focusing on the biological aspects of physical or psychological dependency. This view typically confines the idea of addiction to cases of substance abuse and dependency, and attempts to pinpoint the basis for addiction in terms of changes in brain circuitry and the chemical action of reward neurotransmitters such as dopamine and serotonin. The medical model also highlights the biological reality of withdrawal symptoms when the addictive substance is removed. A second model, the psychiatric model, looks at addiction somewhat more broadly as a manifestation of unresolved psychosocial or emotional conflicts that lead to compulsions or poor impulse control; often this is broadened to include the family, social or cultural context. A third model, which we might call the autonomy model, rejects the medical and psychiatric models as too deterministic and incompatible with the existence of free will.  This model takes addiction to be fundamentally a question of personal responsibility and choice. Finally, behavioral models do not necessarily take a position on the origins of addiction, but look instead at how addictive behaviors can be modified and eliminated. Of course, there are many variations and combinations of these models of addiction.

Varieties of treatment. Depending on which model is favored, different treatments variously emphasize medical detoxification and the use of pharmaceuticals; individual, family, group or residential rehabilitation counseling; recognition of personal responsibility; or various modalities of behavior modification. Under the medical model, pharmaceuticals are often prescribed for detoxification and the relief of cravings.  While drugs may in fact help reduce cravings in the short term, they can create their own problems of side effects and substitute addictions. Antagonist drugs, which block receptors for “reward” transmitters such as dopamine, are often unpleasant and create incentives to quit or circumvent treatment, and they invite relapse once they are discontinued. Typical success rates for drug and alcohol detox rehab programs, which combine medical detox and psychological or psychiatric treatment, have been cited to be as low as 2-20 percent. One such program, Narconon, claims a success rate of 76%, but this figure has been challenged as being vastly overinflated and based upon methodologically flawed statistics. As with many similar programs, Narconon insists on the importance of getting treatment away from the normal work-home environment: :

One thing is for sure if you are trying to break a habit such as drug addiction, a change of environment should be at the top of the list as far as solutions. Due to these factors, attending a drug rehab close to home is seldom the correct treatment option for chronic drug abusers. It is extremely therapeutic to be distanced from the people they used drugs with, drug dealers, and the surroundings that can continue to stimulate their past addictive behaviors.

As we’ll see shortly, it is precisely this key assumption that is questioned by cue exposure therapies.

Behavioral therapies. In essence, behavioral approaches look at addictions primarily as conditioned behavioral patterns that are strongly reinforced, but from which the addict nevertheless still has some motivation to escape. Behavioral therapies tend to divide into two camps: those which employ classical and operant conditioning to directly modify behavior by changing the reinforcement patterns; and those which supplement the conditioning techniques, or replace them entirely, with a cognitive element, following the model of Cognitive Behavioral Therapy (CBT).  The cognitive element typically involves actively thinking about ones behavior, and reflecting on whether or not it is based upon rational or empirically valid assumptions. For example, CBT may treat depression, anxiety, or phobias by challenging an individual to consider whether one’s worst fears are in fact likely to happen, what one is giving up by maintaining the present behavior, and what one stands to gain by stopping it.  Often meditation, mindfulness, and notions of self-efficacy are involved in these cognitive approaches. Examples of the application of CBT to addiction are Alan Marlatt’s Relapse Prevention Therapy and also his Mindfulness therapy; and Aaron Beck’s Cognitive Therapy of Substance Abuse.

However, overcoming addiction may not be all that susceptible to “reasoning” and reflection. Addictive cravings are often incredibly powerful and tend to overwhelm rational thinking.

Cue exposure therapies. There are two very different approaches to treating addiction by behavior modification:  stimulus avoidance and cue-exposure therapies. While they are both considered “behavioral” treatments, they are in fact polar opposites! The stimulus avoidance therapies involve training the individual to avoid exposure to the stimulus. In practical terms, this means abstinence. It  is the approach taken, for example, by Alcoholics Anonymous. A core assumption of AA is: “Once an alcoholic, always an alcoholic”.  Those who take this view claim that it is impossible, or highly risky, for an alcoholic ever to return to moderate drinking. AA has a good success rate, but it tends to require a strong “spiritual” commitment, and can be sabotaged by relapse if the recovering alcoholic or addicts takes even a single drink.

There is an emerging area of research, however, which takes issue with the stimulus avoidance school of thought, and supports the idea that addictions can be replaced by normal responses to behavioral cues, using cue exposure therapy, sometimes called response prevention therapy.  And even more radically, the treatment works best if carried out in the most realistic context of the daily life patterns of the addict.  This completely contradicts the central assumption of Narconon in the above quote!

For a full explanation of the psychological basis and technical terminology of reinforcement theory, I would recommend reading the Psychology page of this blog, which provides useful background on the work of Pavlov and current applications by behaviorists such as Daniels and Pryor in the use of cue exposure as a general method for extinguishing behaviors.  In short, the essence of cue exposure therapy is to extinguish the addictive behavior by allowing the addict to be exposed to normal cues or stimuli that typically precede the addictive behavior, but preventing that behavior from getting underway. This clearly leads to significant discomfort and even withdrawal symptoms in serious cases.  However if repeated frequently enough, and in the presence of a sufficient variety of cues and contexts, cue exposure therapy can be very successful in extinguishing addiction.  Even more importantly, there is evidence that is is successful in preventing relapse over the longer term.

Furthermore, cue exposure therapy is a general approach to addiction treatment. It works not only in treating “chemical” addictions of substance abuse, but addictive behaviors more generally.  There are studies showing its effectiveness with treatment of drug and alcohol addiction, tobacco addiction, and eating disorders. For example, using cue exposure and response prevention, combined with gradualism may be more effective than going “cold turkey” for learning to permanently stop smoking. Other studies show that cue exposure therapy is more effective than a “self control” based cognitive behavioral approach in treating bulimia.

What makes cue exposure succeed? Despite encouraging data of the effectiveness of cue exposure therapies in both addiction cessation and relapse prevention, it is not always successful. A recent review article in the journal Addiction, by Conklin and Tiffany of Purdue, provides an excellent meta-analysis of 18 cue exposure therapy for treating a range of addictions–including treatments for addiction to alcohol (N=5), nicotine (N=5), cocaine (N=1), and opiates (N=6).  The review includes a careful analysis of why cue exposure therapies in many cases fail, why they often succeed, and what specific factors determine their degree success. Conklin and Tiffany not only review the clinical and field studies with human subjects, but also cite the most current animal research on addiction extinguish to buttress their analysis. This is an academic paper, but clearly written and accessible to the intelligent layperson. For anyone struggling with addiction and willing to consider cue exposure therapy, I highly recommend reading this paper carefully to absorb its many insightful lessons.

The cue exposure treatment studies varied considerably in their design and execution. In about half of them (mainly the drug studies), the participants were abstinent during cue exposure.  In one study (with alcohol dependence),  a moderate drinking goal was encouraged by providing “priming” doses of alcohol, with the the prevention of drinking more than one drink, and this behavior was practiced both “inpatient” and as outpatient “homework”.  Cue exposure varied from real “in vivo” cues to surrogate video, audio, and even “imaginal” cues just pictured in the mind.  The frequency of cue exposure varied greatly — from a single cue exposure (e.g. smelling a glass of alcohol for 3 minutes) within a single session, to multiple, frequent exposures per session over 10 consecutive days of cue exposure sessions, to periodic exposure sessions spaced in time over weeks, with follow up over 6-12 months.

In their review article, Conklin and Tiffany identify 4 main “threats to success” (and corresponding success factors) that explain both why cue exposure did not work well in some cases and where it either was, or could be made, more effective.  Before summarizing these success factors, I think it is important to note one key insight they highlight regarding recent learnings from animal research:

Rather than simply trying new things in an effort to discover the optimal parameters for use in cue-exposure addiction treatment, ideas for improving treatment can be directly informed by recent animal learning research focusing on extinguishing learned behavior…ideas about extinction have changed considerably since cue exposure was first introduced as a treatment for addiction. For many years, extinction training was believed to lead to a weakening of the initially condition CS-US association…However current concepts about extinction resemble more closely the original ideas of Pavlov (1927), who postulated that repeated unreinforced exposure to the CS does not break the original CS-US learning, but rather serves to mask it…Therefore, the conventional notion that extinction is unlearning has been replaced with the position that extinction is new learning, that is, during extinction, CS-US learning remains intact, but new associations develop to the original CS. (p. 159)

This is a crucial insight!  The original addictive response to stimulating cues will never die by itself, merely by not reinforcing those stimuli.  Rather, it is important to learn new behavioral responses to those old cues which come to “mask” or dominate the the old responses.  Cue extinction is an active process, not a passive one!

Now let’s turn to the specific threats to the success of cue extinction which have been identified by Conklin and Tiffany:

1. The renewal effect occurs when a behavior is successfully extinguished in one limited context or set of cues, but re-emerges in response to a different context or cues. This is a common problem in treatment, because the treatment context often differs in significant ways from the “real world”.  Conklin and Tiffany give the example of a heroin addict who gets inpatient extinction treatment in a hospital room, but resumes shooting up at home–a different context, with different cues. The same conditioned stimulus (CS)– for example seeing or handling drug paraphernalia, or being stressed–can acquire a different “meaning” in the two different settings. Cues can be rich, subtle and varied: the action of lighting a cigarette with a match, handling of drug equipment, or the smell, the size and feel of surroundings, people, and the time of day. There are a number of important ways to deal with this problem.  First, the extinction training should as much as possible occur in the “original conditioning context”, that is the real-world context in which the addiction was acquired and has been developed.  Second, given the fact that most addictions are reinforced by a rich set of cues and multiple contexts, the extinction training should occur in several distinct contexts, and then re-tested in the original context.  According to the authors, “Apparently, whereas conditioning generalizes readily, extinction is largely context-dependent”. (p. 160).
2. Spontaneous recovery occurs merely with the passage of time, even when a behavior is initially extinguished successfully.  The addiction can re-emerge by itself days, weeks, or months after being apparently terminated. Dealing with spontaneous recovery requires consideration of the “temporal spacing” of cue-exposures. Here, the authors cite a number of animal studies for guidance. In one such study, extinction occurred more rapidly and successfully when the cues were given as a series of short exposures over time instead of as a single “massed” presentation. Other studies found that extinction success was optimized by allowing longer intervals of time between exposure sessions, combined with more frequent in-session exposures. This was also reflected in the human studies. Based on this research, Conklin and Tiffany give the following guidelines:
   • Within each session, the cue should be presented several times to ensure complete extinction of “responding”, defined as as subjective desire or objective physiological or behavioral response
   • Within-session exposures should be separated by enough time to allow some recovery of responding between exposures
   • Enough time should be allowed between sessions to allow for spontaneous recovery of responding, and therefore further extinction at each session
   • The number of extinction sessions needed depends on the individual’s pattern of responding, which can vary considerably among individual subjects
3. Reinstatement occurs after a conditioned stimulus (CS) has been extinguished, by presenting the unconditioned stimulus (US) alone.  For those not familiar with this terminology (which is described in more detail on the Psychology page of this blog), the US is the immediate agent that produces the addictive “high”, e.g. the drug, tobacco, alcohol or food itself, whereas the CS is any cue which becomes associated with it, e.g. seeing or handling a bottle or cigarette, or visiting a bar or drug dealer. So in reinstatement, the former addict has learned not to respond to the environmental context and cues, but for one reason or another encounters the addictive substance in a new context, re-igniting the addiction anew and leading to potential relapse after even a single new exposure.  Here, the research on prevention is very interesting. Relapse in such situations can apparently be prevented or quickly cut off by immediately exposing the lapsed addict to unreinforced exposure to the new context alone (without the US).  So if your addiction to sugar or alcohol is re-ignited by inadvertently or unwittingly consuming a food that stealthily contains this offending substance, expose yourself to eating other foods (without the addictive substance) in the same place and with the same cues, on more than one occasion, and the relapse will be forestalled.
4. Behavioral cue conditioning is one of the more subtle, but insidious threats to successful extinction. If the addiction is based upon classical conditioning (that is the addictive behavior is a direct “conditioned response” (CR) to one or more conditioned stimuli (CS), then deconditioning by extinction training has an excellent chance of success.  However, in many cases of addiction the CS indirectly elicits behaviors that precede the direct addictive response, and these behaviors themselves act as secondary “discriminant stimuli” which provoke the addictive response independently of the CS.  For example, for an alcoholic, the CS may be a bottle of booze. By the principles of classical conditioning, the appearance of the bottle can be extinguished as a cue for the urge to drink (the CR or conditioned response), by exposing the alcoholic to the bottle and not allowing drinking. However, in the normal context, the alcoholic engages in certain active routines or behaviors, such as pouring the alcohol into a glass, handling the glass, drinking from the glass, etc. These behaviors in themselves serve as independent cues, beyond appearance of the bottle itself, that stimulate the desire for the alcohol.  So it is not just the sensory stimuli that need to be extinguished, it is also the behavioral cues.  Overlooking this reality turns out to be a major flaw of many of the less successful treatments reviewed by Conklin & Tiffany. In these flawed treatments, the cue exposure sessions dealt with sensory cues alone. The authors found the best treatments involve extinction of active behaviors.  For example, one study had smokers actually light cigarettes and take non-inhaled puffs.  Another study had heroin addicts go through an actual cook-up procedure and handle all their paraphernalia, without allowing follow-through to actually administering the drug. While to an adherent of the “abstinence” approach such therapies may seem unduly risky, the science actually supports such realism as being the most effective way to immunize an addict against relapse.

There is some recent evidence from a study by researchers at McMaster University and the University of California at San Francisco that takes this approach even further.  In cases where the goal is moderation and not abstinence, it is important the the cue exposure involve actually take small doses (e.g. one drink), while preventing any follow up drinks, to re-train the response.  This is based on observations that addicts or alcoholics respond to a small dose as a cue that “more is coming”. Without this type of conditioning, there may be increased risk of relapse.  Again, “you get what  you train for”.

Conclusions. In short, cue exposure therapies will not work if they are confined to small number of artificial exposures within a single limited context, especially if it is significantly different from the context where the addictive behavior was “learned”.  The exposure should be rich and varied, repeated both within a cue exposure session and at subsequent sessions while allowing an adequate time interval both between in-session exposures and between separate sessions to allow “responding” or partial re-emergence of the desire or craving. Cue exposure therapy should not involve mere passive exposure to sensory cues but should  include a realistic “behavioral” component which is practiced without allowing the reinforcement itself to occur. Finally, it is important to keep in mind that extinction is not a matter of passively “unlearning” an old behavior by just not responding, but actively learning new substitute behaviors for responding to the original cues and contexts; adding a degree of “counter-conditioning” is useful here (see the discussion of counter-conditioning on the Psychology page of this blog.

What does this mean for you? Is there an addictive behavior or a bad habit you would like to overcome?  Are you willing to try cue exposure therapy.  If so, observe and think about the sensory and behavioral cues that precede your behavior and how you could design your own cue exposure sessions to help extinguish the behavior.

What does this mean for me? I stated at the beginning of this post that I would do something unusual. Rather than writing this post purely as a scientific report or as an “advice column” to others, I am going to put it to the test on myself.  In the tradition of self-experimentation inspired by Seth Roberts, I am going to put my money where my mouth is and try it on myself.  I have used cue extinction already as the basis for deconditioning myself from having a strong appetite for food (at certain times of day), for cutting back significantly on certain favorite desserts (such as ice cream), and for giving up caffeinated coffee (but still enjoying the occasional cup of decaf).  However, I retain a certain fondness for alcohol.  I’m not an alcoholic and and don’t believe I have a drinking problem, but I drink more than I would like to and find myself craving certain drinks before dinner almost nightly. My favorite drinks, in order, are: (#1) B&B cognac liquor on the rocks; (#2) Manhattan cocktail; (#3) beer; (#4) red wines, especially Pinot Noir.   About a year ago, I cut back to a frequency of 1-2 drinks per week, but recently this has crept up to a nightly drink, and I find myself really looking forward to it after work.  It is a real pleasure and stress reliever, and I don’t want to cut back, but I know I should.

So you’ll find a record of my experiment, starting today (Thursday, April 14), on my personal page on the Discussion Forum.  At this point, my goal is not total abstinence, but cutting down to a maximum of 1-2 drinks on 1-2 nights per week. Wish me luck!

1. Flavor-calorie dissociation as advocated by Seth Roberts in his Shangri-La Diet
2. Sensory-specific satiety, as advocated in David Katz’s Flavor Point Diet
3. Tastants, another approach to sensory-specific satiety, as advertised in Alan Hirsch’s Sensa Weight-Loss Program.
4. Odor inhalers, a third approach based on sensory-specific satiety, as described in Alan Hirsch’s book Scentsational Weight Loss, and marketed by him as ”diet pens” offered by SlimScents

At first, some of these approaches appear to be mutually incompatible. The Shangri-La theory argues that strong or familiar flavors enhance appetite when they become associated with caloric foods.  The other three approaches, by contrast, claim that intense flavors or aromas suppress appetite, based upon the principle of “sensory-specific satiety”, whereby an increase in the intensity of a single flavor or odor induces satiety. However, on closer examination, all of the above theories are consistent with one another, as I will try to show. Furthermore, they each provide some useful clues about how to achieve a long term weight loss and relief from hunger cravings by paying attention to the role of flavor and other food cues.  Finally, as I will attempt to persuade you, only one of the above diets is truly a type of Deconditioning Diet that can lead to long term, permanent reduction in appetite, based on the principles of Hormetism.

This post is one of the longer, more complex ones I’ve written so far. It’s almost like a full chapter in a book.  For that, I apologize. But if you hang in there and try to follow the twists and turns in the science, I think at the end of this post you’ll find that certain puzzle pieces start to fit into place, leaving us with a framework that helps us to figure out some truly effective new methods of controlling appetite and weight. If  you want to skip to the punch line, you can find the simple explanation at the bottom of this post, below the dotted line, under the heading “A Unified Explanation of Flavor Control Diets” and “Lessons Learned”.  But for those who want to understand the science, read on….

I’d like to briefly review these weight loss programs and the underlying theoretical explanations for two reasons. First, I think that while the diets are useful, the explanations offered as to why they work are in several instances incorrect. I believe that the insulin response theory of appetite provides a more adequate explanation, and one which resolves the apparent contradiction between the two theories. Second, and more importantly, I think the insulin response theory of appetite, in combination with the philosophy of Hormetism, provides a scientific basis for the Deconditioning Diet.  As detailed on the Diet page of this website, the Deconditioning Diet is a weight loss program that offers the prospect of permanent and lasting changes to appetite and long term weight loss without dependence on consuming or using specific dietary agents or devices, such as is required by all four of the above flavor control weight loss methods.

The Shangri-La Diet. I credit Seth Roberts’ book by this name for first making me aware of the connection between flavor, appetite and weight control.  I tried the diet and it works.  I lost 10 pounds rather easily by using Roberts’ concept of flavorless calories to suppress appetite. Roberts discovered his diet while vacationing in France.  He tried some French sodas with “unfamiliar” flavors and found they suppressed his appetite almost totally. He found himself skipping meals or forgetting to eat, and he lost weight on the trip. He hypothesized that it was the unfamiliar flavors in combination with the calories from sugar that led to his appetite suppression. When he got home, he figured out that consuming sugar water with no added flavor would be as effective and simpler than using unfamiliar flavors.  Consuming daily fructose water left Roberts hungry enough to eat only “about one meal every two days”, and he steadily lost about 2 pounds a week, dropping from 185 to 150 pounds in short order. He satisfied his desire for non-caloric flavors by drinking tea and chewing gum, and his desire for texture by consuming  small portions of crunchy or chewy snacks like apples, nuts, or jerky.

Roberts then generalized his diet to stipulate ingesting small 200-calorie doses of flavorless calories, at least an hour before or after any meal.  “Flavorless” in this case means undetectable by the nose.  The sweetness of sugar appears not to count as a flavor, because it is detected only on the tongue and not by the nose.  (A test of whether something is a flavor is that it will become undetectable if you pinch your nose while tasting.  Sweetness, saltiness, and sourness are detected by the tongue only).  So besides sugars like sucrose and fructose, Roberts found that vegetable oils work well, particularly low flavor oils like extra light olive oil (ELOO) and certain nut oils.  On his website,  Roberts hosts a forum where an on-line community of SLD diet followers have extended the methodology to include variations such as “nose clipping” (wearing a nose clip or pinching your nose to suppress flavors while eating regular foods) or formulating various flavorless drinks and meals.  The SLD diet has clearly been successful for a great number of people,  many who have found it to be the least painless way to regain control of their eating and lose a large amount of weight, with great flexibility, no restrictions on the types of food you can eat, no calorie counting, and no sense of deprivation.

Roberts’ theory of weight control can be summarized as follows:  Foods with a weak flavor-calorie association will lower your body fat set point and cause you to lose weight; foods with a strong flavor-calorie association will do the opposite. He supports his theory of flavorless calories with evidence from the usually disparate fields of weight control (physiology) and associative learning (psychology). From weight control theory, he draws on the lipostatic theory of Gordon C. Kennedy.  Kennedy conducted experiments with rats in the 1950s which suggested that weight or body fat is homeostatically controlled to a relatively constant “set point”. When rats were fed less calorically dense food, they first lost weight, but then adjusted by eating more of the low-cal chow to re-establish their “set point”, just as a thermostat will turn on a heater whenever the temperature of the building drops below its set point. Kennedy’s experiments were backed up by similar studies in other animals and humans. In particular, Roberts cites a series of experiments by Dr. Michel Cabanac, a physiology professor at Laval University in Quebec. Cabanac worked with human subjects, who generally find glucose water pleasant to sip. Cabanac slowly pumped glucose water directly into the stomachs of his subjects, and then had them sip sugar water. For the subjects who had sugar injected into their stomachs, the sipped sugar water became less pleasant, and they felt full. In a follow up experiment, subjects first lost 8 pounds by just eating less of their usual diet, then the glucose injection experiment was repeated.  This time, the injected glucose water no longer reduced the pleasantness of the sipped sugar water, and the subjects remained very hungry. Roberts takes this to indicate that the increased appetite of this second group was caused by their actual weight being below their “set point” weight. In a further experiment, Cabanac found that letting subjects consume as much as they wanted of a restricted bland liquid diet let to significant weight loss without hunger.  And one of Cabanac’s students found even faster weight loss and appetite suppression by directly injecting the liquid nutrition through a stomach tube. This suggested to Roberts that flavors raise set point, and lack of flavor (as in direct injection of sugar or food to the stomach) reduces set point.

From associative learning, Roberts draws upon the very work of Pavlov that I have cited (for different reasons) on the Psychology page of this site.  He cites several experiments that appear to establish the general principle of flavor-calorie associative learning.  In one study with rats, Dr. Anthony Sclafini, a psychology professor at Brooklyn College in New York, allowed rats to drink water with two different flavors.  Whenever they sampled Flavor 1, a caloric starch compound (Polycose) was injected into their stomachs, but when they drank Flavor 2, plain water was injected into their stomachs.  The rats developed a strong preference for Flavor 1, and this preference persisted several days even after the injections were stopped.  Since they could not “taste” the injected Polycose, Sclafini and Roberts take this to provide flavor-calorie associative learning.

Putting these two lines of research together, Roberts concludes that consuming calories with familiar or strong flavors tends strengthen flavor-calorie association and preference for those flavors, and will raise the weight set point, whereas consuming flavorless calories or calories with unfamiliar flavors tends to reduce both the flavor preference and the set point.  Roberts and his followers have used the hypothesized connection between flavor-calorie association and body fat set point to make predictions and extend the diet. For example, Roberts predicted and confirmed that appetite suppression and weight loss can also be achieved by consuming foods with unfamiliar flavors, so one variation of SLD is to add “crazy spices” to foods to break the flavor-calorie association, or by using nose-clipping to suppress detection of flavors while eating.

However, the success of the SLD diet in itself does not prove that Roberts’ explanation for why it works is correct. I believe that Roberts explanation is incorrect for several reasons:  (1) the set point theory is not empirically testable;  (2) Roberts learning theory is based on a misunderstanding of Pavlov’s theory of associative learning; (3) Roberts’ learning theory makes several false predictions and fails to explain other facts about weight loss; (4) there is an alternative explanation for why SLD works that can better explain these other facts about weight loss.  I’ll take up these criticisms in order.

Lipostatic set point theory of weight control. According to Roberts, if you weigh less than your set point, “you will be hungry and think about food” and the bigger the gap, “the more you will think about food, and the more food it will take to feel full when you eat.  It is nearly impossible to weigh much less than your set point for a long time–the hunger becomes unbearable.”  (SLD, p.9) Similarly, if you weigh more than your set point you will not be hungry and “When you eat, you will feel full rapidly.” It is apparently not your weight, but your body fat content, that is compared with a set point. “When your body-weight regulatory system detects that you have less fat on your body than your set point, it makes you more hungry than usual between meals and increases how much food you need to eat to feel full.” (SLD, pp. 41-2)

And yet the lipostatic set point does not seem to operate like temperature set point on a thermostat. Whenever the temperature is below the thermostat set point, the heater turns on immediately, or after a short delay. And whenever the temperature is above the set point, the heater never turns on–until temperature drops on its own, or with the assistance of air conditioning. But this is not the case with body weight “set point”. When you weigh 8 pounds less than your set point, you don’t eat continuously in one session until the set point is reached. Likewise if you weigh 8 pounds more than your set point, you don’t totally stop eating until your weight drops to the set point level. Instead, most people have a certain rhythmic frequency of eating alternating with not eating. Something else regulates this rhythm of meals even when we far from set point. (As I’ll suggest below, that “something” is the hormone insulin).

Roberts acknowledges that set point is not fixed, and he posits that your set point is directly influenced by what you eat. He explains that between meals, your set point goes down gradually, and the higher your set point, the faster it goes down. But, according to Roberts, your weight goes down faster than your set point, which is “why not eating causes hunger–and why diets that deprive you of food don’t work.” Eating foods with flavor-calorie association will immediately raise set point; and the stronger the association, the greater the increase in set point.

But this is an odd sort of set point that is never really set! The very thing that is controlled by set point (eating) itself causes the set point to change. It is as if a thermostat setting were itself influenced by the temperature in the house, rather than by the intentional decision of the house occupants. The set point concept starts look very flexible, with a lot of external influences and circular feedback loops. (It reminds me of how epicycles were added to the Ptolemy’s geocentric theory of the solar system in order to explain the apparent zigzagging of observed orbits of plants and stars around the earth, until Copernicus eventually came up with the simpler heliocentric theory in the 16th century). If set point is always changing, how could you verify this? It just seems like a convenient theoretical entity that can never be proven or disproven. Roberts’ claim that highly flavored caloric foods cause weight gain because they are “high set point foods” is an example of this circular reasoning.

There is also one other weird aspect of the lipostatic theory of weight control.  It seems to commit us to the view that each of us has a “natural” set point weight or fat mass, which we cannot change.  Unless, that is, we following the Shangri-La Diet and we commit ourselves to eating bland foods, at least periodically–forever. If we are born with a “fat” set point weight and eat flavorful caloric foods, we are destined to get fat. Naturally thin people who can eat flavorful foods are just lucky, because…they are born with a low set point.  Somehow, I doubt this.

This does not mean we should throw out the concept of a set point.  We just have to pick a physiologically verifiable set point.  True examples of set points and homeostasis are blood pH and body temperature which are controlled in a narrow range, under normal circumstances. There is not anything that you can do to alter these set points, and nor would you want to do so. Fevers, hypothermia, and ketoacidosis are indicators of disturbance or pathology, and the organism works hard to restore temperature or pH to the healthy set point values in such cases. Furthermore, the physiological basis of these homeostatic mechanisms for regulating body temperature and blood pH are well known. So I think that extending the set point concept to such a variable quantity as body weight is neither legitimate nor useful, and there burden of proof should be on its advocates to demonstrate an empirical basis for it.

Roberts does acknowledge physiology when he claims that set point is related to the concentration of leptin in the in the bloodstream:

In order to regulate the amount of body fat, the brain must be able to know how much body fat you have, just as a thermostat needs a built-in thermometer to keep track of the room temperature. Leptin serves as the brain’s body-fat thermometer: The concentration of leptin in your blood tells your brain how much fat is in your body. Leptin is produced by fat cells. When your body fat goes up, so does the amount of leptin in your blood.  When your body fat goes down, leptin goes down.  (SLD, p. 143)

This is getting closer to a bona fide physiological explanation. In fact, I agree that hormones drive weight control, I just think that Roberts has chosen the wrong hormone. There are two problems with choosing leptin. First, while leptin does play a key role in signalling satiety to the brain, it is not the whole story. First, the leptin signal does not always work. People can become resistant to leptin.  The brain can’t always “hear” leptin even when it is elevated, leading people to overeat. This is especially true with obese individuals.  The leptin signal can also be blocked by ingesting a meal high in carbohydrates, since carbohydrates lead to high triglyceride levels in the bloodstream, and this can block the leptin signal, again leading to overeating. Furthermore, leptin is not the only player in hunger signaling. The brain integrates the signal from leptin with that of other appetite signallers, including hormones such as ghrelin, and neurotransmitters such as neuropeptide Y, serotonin, dopamine and various opioids.  We need to look further up the stream to the root cause of hunger, not the “messengers”.

Another problem with the leptin theory is that is inconsistent with at least two observational facts:

1. The observed variability in body weights in the population. Leptin is known to increase in fat individuals and decrease in lean individuals.  So lean individuals, who have lower levels of leptin, should be hungry and want to eat more, until their leptin reaches a “satiating” level.  However, that would seem to rule out the existence of lean people. Everyone should eat until their leptin level reaches the “normal” level.  And yet that is absurd, because most lean people are not ravenously hungry.  That implies that every individual can have a different “normal” leptin level.  That is in fact the case, but then it removes leptin as a homeostatic regulator of weight or body fat.
2. The suppression of hunger observed during extended fasting. After an initial period of cravings, light-headedness or other hypoglycemic response, people who are fasting for extended periods of 12-24 hours or longer commonly report appetite suppression and a surge of energy.  This cannot be explained by the lipostatic set point theory or Roberts version of it. To repeat what I wrote above, according to Roberts, your weight goes down faster than your set point, which is “why not eating causes hunger–and why diets that deprive you of food don’t work.” But if weight is dropping faster than set point during fasting, your hunger should increase monotonically, that is, it should get steadily more intense, without dissipating.  Yet that is not what happens.  After a period of adjustment, as insulin drops, glucagon rises along with adipose tissue lipase, and adipose tissue begins releasing free fatty acids into the bloodstream, while the liver breaks down glycogen into glucose and proteins into glucose via gluconeogenesis.  So a constant level of glucose in the bloodstream is restored, and there is no sense of deprivation or “unbearable” hunger.  Most people who fast, including myself, find it quite pleasant.  I think the bad rap on fasting comes from people who have not studied the physiology of fasting and either haven’t tried it, or haven’t given their bodies enough time to adapt.

The glucostatic theory. There is a much better alternative to the lipostatic theory of hunger and weight regulation:  namely, the glucostatic theory of Jean Mayer, as it has been developed into a fuller theory of the homeostatic regulation of blood glucose by the hormone insulin. While there are many hunger signaling compounds, ultimately these signals are either responding to or predicting what is happening or likely to happen to blood glucose concentrations. In the glucostatic theory, there is also a set point that controls hunger, and it is blood glucose concentration. According to the glucostatic hypothesis, there is no body fat “set point” that our body attempts to defend, no “natural” level of fatness or leanness. This is evidenced by the fact that it is possible to gain or lose a lot of weight and main these changes. Whether we are fat or lean, our body strives to maintain glucose concentration within a physiologically tolerable range of about 70 to 150 mg/dL. Below that level, hypoglycemia sets off hunger pains, headaches and–in extreme cases–shock and coma. Above that level, there can be both acute problems with high blood glucose and chronic problems with elevated blood glucose, leading eventually to hyperinsulinemia and diabetes. There is an excellent discussion of the glucostatic and lipostatic theories of weight control in Chapter 24 of Gary Taubes’ Good Calories, Bad Calories, delineating further problems the lipostatic theory.

This is not to say that weight is not remarkably stable in most people for long periods of time. But this stability is not the result of homeostatic control.  Rather than being a “set point”, body fat may be a “settling point”.  Taubes is very articulate on this point:

Life is dependent on homeostatic systems that exhibit the same relative constancy as body weight, and none of them require a set point, like the temperature setting on a thermostat, to do so. Moreover, it is always possible to create a system that exhibits set-point-like behavior or a settling point, without actually having a set-point mechanism involved. The classic example is the water level in a lake, which might, to the naive, appear to be regulated from day to day or year to year, but is just the end result of a balance between the flow of water into the lake and the flow out. When Claude Bernard discussed the stability of the milieu interieur, and Walter Cannon the notion of homeostasis, it was this kind of dynamic equilibrium they had in mind, not a central thermostatlike regulator in the brain that would do the job rather than the body itself.

This is where physiological psychologists provided a viable alternative hypothesis to explain both hunger and weight regulation. In effect, they rediscovered the science of how fat metabolism is regulated, but did it from an entirely different perspective, and followed the implications through to the sensations of hunger and satiety. Their hypothesis explained the relative stability of body weight, which has always been one of the outstanding paradoxes in the study of weight regulation, and even why body weight would be expected to move upward with age, or even move upward on average in a population, as the obesity epidemic suggests has been the case lately. (GCBC, pp. 428-9)

In effect, the apparent stability of weight results from a relative constancy in many factors–hormone activation, food intake, physical activity–any change in which can shift this balance to a new stability point.

The glucostatic theory also provides explain how appetite can change on a minute-by-minute basis. Typically, a drop in blood sugar is associated with hunger and the initiation of eating.  While blood sugar can drift down on its own, the more usual scenario is that food cues such as aromas, or the time of day, lead  to a psychologically triggered secretion of insulin are the immediate causes of a dip in blood sugar, with its attendant hunger signals.  This usually occurs at meal times because of prior conditioning.  Blood sugar can also drop when the body is running low on glycogen and is having difficulty switching over to fat or ketones, or when blood sugar is depleted by exercise or other activity that outstrips the ability to resupply glucose from the tissues.

Unlike blood glucose and insulin–which can change by the minute and correlate well with the well known rhythms of appetite and satiety–body fat and body weight change much more slowly, and therefore do not seem to be good candidates for direct control, as required by the set point theory of weight regulation.

Associative learning. There is a second problem with Roberts’ explanation of why the Shangri-La Diet works. One of Roberts central claims is that body fat set point is influenced by flavor-calorie association, and that the strength of the association between flavor and calories comes about by means of associative learning. In this regard, Roberts explicitly invokes Pavlov to explain why the the SLD requires that flavor and calories be detected at separate times:

In Pavlov’s experiments, the bell was the signal and the food was the outcome.  The food was given at the same time the bell was turned off.  Had the food been given many minutes after the bell was turned off, the dog would not have associated them  at all. (SLD, p. 47)

Roberts further supports this contention about timing by citing experiments with rats indicating that “a flavor-calorie association was learned even when there was a thirty-minute gap between eating the flavor source and eating the calorie source” (p. 70), but a one-hour gap was sufficient to prevent such a learned association from forming. The flavorless calorie window of one hour stipulated for the SLD is based on the Pavlovian principle that “the more delayed the outcome, the weaker the association”.

But I believe Roberts’ interpretations and conclusions regarding Pavlov’s finding are not correct here. First, Pavlov did in fact show in his experiments with dogs that a delay between a stimulus such as a buzzer, and a delayed feeding would merely reinforce a delay in the salivation. The dogs would wait the required amount of time:

As his technique became more practiced, Pavlov’s laboratory began investigating the canine sense of time. After a dog was trained to salivate at a flash of light, the delivery of the stimulus was postponed by three minutes. Before long, the dog learned to anticipate the delay. Three minutes after the signal, the animal’s mouth would water. (The Ten Most Beautiful Experiments, p. 132).

But second, note that Roberts in the previous quote is talking about an association between the bell and the food presentation (two stimuli). That is indeed associative learning, because both the bell and the food can be perceived. The bell and food repeatedly occur together, and become psychologically associated.  This association is strengthen considerably by reinforcement.  The bell is a conditioned stimulus (CS) and the food is an unconditioned stimulus (US) and classical conditioning is all about associating CS with US, by virtue of reinforcing the unconditioned response (UR). In this case the UR is salivation and an increase in appetite, and the reinforcement is the rise in the dog’s blood sugar that occurs after it eats the food. (If the food was taken away before being eaten, there would be no reinforcement).

Yet in his explanation of why the Shangri-La diet works, Roberts talks about an “association” between flavor and calories. However it is a misapplication of the concept of associative learning to speak of “associating” a perceivable entity (flavor) with an unperceivable physiological reaction (detection of “calories”). The calories cannot be directly perceived by the sensory apparatus. Rather, the ingestion of food results in a physiological response, a rise in blood sugar, and its further consequence, secretion of insulin. There is a perceivable consequence of the calories (hunger), which is possible to associated with certain stimuli.  But that is not what Roberts is claiming. He says that we learn to associate flavors with calories, not with hunger or satiety. The relationship between a perceivable stimulus and a physiological response, if reinforced, gives rise to classical conditioning.  This is distinct from associative learning, in which two perceivable stimuli become associated with each other when they occur together repeatedly.

Put another way: it is not strictly correct to say that people “learn” to make “associations” between flavors and calories, especially since they are not directly aware of the calories (other than by reading food labels). All we can discern is whether or not the flavorful food provides relief from hunger. Roberts sometimes seems to conflate awareness of calories–a requirement for associative learning–with physiological detection of calories. But physiological “detection” by the digestive system is not associative learning.Strictly speaking, it is not a flavor-calorie association, but rather an association between flavor and the satisfaction of appetite. An even better way is to formulate this as a stimulus-response relationship, since the primary response is physiological and not conscious. In this case direct response to the stimulus of flavor is insulin secretion, and indirect responses are blood sugar and appetite.  Pavlov primarily studied the conditioning of stimulus-response relationships; the associative learning was merely an explanation for how a secondary, conditioned stimulus could become secondarily associated with the primary unconditioned stimulus.

Even if we were to accept Roberts position that unconscious detection of caloric foods by the digestive system is sufficient for calories to play a role in “associative learning”, we are left without an explanation of how calories per se can be detected.  In this regard, the digestive system does not recognize all “calories” as a monolithic unit of food, as Roberts seems to suggest.  His explanation of how low carb and “good carb” diets work overlooks significant differences in how calories in different types of macronutrients interact with the digestive system. He seems to assume the only difference between carbohydrates, proteins and fats is how quickly they are released and detected:

When a food is digested more slowly, the calories in that food are detected more slowly. Thus there is more of a gap between the signal (flavor) and the outcome (calories). I believe this is why low-carb and good-carb diets work: They replace foods  that are digested quickly, such as bread, with foods that are digested slowly, such as vegetables. The foods that are digested more slowly have weaker flavor-calorie associations. They raise your set point less.  (SLD, p. 47)

But this does not seem very plausible.  Low molecular weight oils can be digested and absorbed as least as quickly as most starches. The reason that oils lead to better appetite suppression and weight loss than simple carbs is not that they are detected more slowly, but rather than they induce little or no insulin response. Furthermore, fats will result in increased appetite in weight if they are combined with even a modest amount of carbohydrates, because the insulin response will cause them to become “fixed” with the glucose to form triglycerides in the adipose tissue. It is critically important to consider the types of macronutrients and how the endocrine and digestive system responds to them alone and in combination.

A better explanation for Robert’s one-hour rule is based on the dynamics of insulin secretion, and the way that this can become conditionally mediated via sensory stimulation of the vagus nerve . When correctly understood in terms of insulin response, the one hour rule should be changed to an asymmetric rule.  In fact, one should only need to wait about 15-30 minutes after ingesting non-caloric flavors before consuming calories, but depending on the meal size, one may need to wait an hour or more before consuming flavors after eating.  This is because the pre-prandial insulin response is shorter and smaller than the post-prandial insulin response.

In fact the one-hour rule must be differentiated even further, based on the macronutrient composition of the calories, and it leads to a number of predictions that diverge from the SLD:

1. Wait at least 15-30 minutes after a flavor or aroma before ingesting carbohydrate containing foods. (This is to allow the pre-prandial insulin response to subside, and blood sugar to renormalize).
2. Wait at least an hour after consuming flavorless carbohydrate-containing foods before ingesting flavors. (This is because the post-prandial insulin is much larger and takes longer to return to baseline than the transient flavor-induced pre-prandial insulin response).
3. The same rules apply to meals which contain large amounts of protein.  Protein is much less insulinogenic that carbohydrates, but large protein meals and certain types of protein are insulinogenic.
4. You can eat fats and flavors together without any worry, because fat is not insulinogenic alone–it requires the presence of a little carbohydrate or a lot of protein to be removed from the bloodstream by insulin.

The flavor-insulin response, which is mediated by the tractus solitarus in the brain and the vagus nerve, is a conditioned response.  It will be strengthened whenever the flavor cue is concurrent or closely followed by a the ingestion of insulinogenic foods, foods which in themselves produce an insulin response when detected by the glucose receptors in the stomach and intestines. Essentially, the flavor-insulin response is a predictive response that readies the digestive tract for food that is coming, by making the food more absorbable. Secreting pre-prandial insulin for a pure fat meal or a small protein meal has no value, and that conditioned response will tend to extinguish. So that leads to another set of predictions. In particular, despite what Roberts claims, fats and sugars should work very differently in the SLD. So here are some predictions made by the insulin-regulated glucostatic theory of hunger, all of which are either not predicted by SLD or are diametrically opposed to what SLD would predict:

1. Consuming pure fats like olive oil or heavy cream should suppress appetite even if they are flavored. This only works, however, if no more than a trace of carbohydrates or proteins.  (This works because fats are noninsulinogenic).
2. Increasing the dose size of oils even to large doses should increase appetite suppression
3. Increasing the dose size of sucrose or glucose beyond the minimum dose, should reduce appetite suppression.  A small amount of sucrose or glucose increases satiety because it raises blood sugar slightly, and flies “under the insulin radar”.  Insulin is not secreted until blood sugar rises above a certain threshold, typically 120 mg/dL or so.  But once it exceeds that threshold, insulin kicks in, and blood sugar drops.
4. Sipping sucrose or glucose slowly will maintain appetite suppression.  If this is done slowly enough, the addition to blood sugar just balances out the amount of blood sugar consumed to meet metabolic needs.  But this is a careful balance.
5. Increasing the dose of fructose, xylitol, erythritol, or other non-insulinogenic sugars should suppress appetite at any dose.

Prediction 4 is consistent with SLD. Predictions 2 and 5 are consistent with SLD, but not predictable from it. Predictions 1 and 3 are contrary to the fundamental assumptions of SLD, and would not be predicted by it.

For anyone who is interested in subjecting SLD to a test, I would be interested in their experience in attempting to verify or refute the above predictions, especially 1, 2 and 3.

The Flavor Point Diet. (FPD). This diet, created by David Katz, is based on the concept of “sensory specific satiety”. Eating a meal with flavors in multiple “competing” categories such as sweet, salty, or savory, somehow stimulates the “appetite center” of your brain, causing overeating. Limiting the flavor categories in a meal or snack to one or two flavor types makes it easier–more rapidly and with less food– for your brain and stomach to reach the “flavor point”, a state of satiety that causes you to stop eating, with less food. This concept is reflected in the popular notion of “multiple stomachs”, whereby you can feel stuffed after eating one course of a meal, but you often seem to find additional appetite for dessert or something different.  The FPD advises you to restrict the number of simultaneous flavors within a meal, but overcomes the potential boredom by allowing you to eat a variety of flavors over the course of a day or week–just not “excessive variety” all at one time.

Katz bases most of his case for sensory specific satiety on the way in which flavors stimulate the production of neurochemicals that activate the hypothalamus:

As soon as you taste food, the sensory information registers in the hypothalamus in the brain, which, depending on the flavor of the food, sends out signals to eat more or less.  Because of this sensory relay system, the appetite center in your hypothalamus can become aroused–and in some cases overly aroused–by how a food tastes. (FPD, p. 4)

As soon as you bite into any food, sensory stimulation of nerve endings on the tongue leads to the release of a number of chemicals, including opioids, into the bloodstream.  You release more opioids–the body’s natural version of drugs like morphine–when you consume foods high in sugar and fat, creating a powerful, neurochemical drive to overeat those foods.  These opioids and other chemicals enter the bloodstream and carry their messages to the hypothalamus, which sends out yet another set of chemicals to regulate appetite. The more flavors your taste buds register, the more stimulated the hypothalamus becomes, releasing the hunger-promoting neuropeptide Y. When you taste a lot of flavors at once, the brain releases a lot of neuropeptide Y.  Meanwhile, in response to the smell and taste of food, your stomach produces the hormone ghrelin, which also stimulates appetite.  It continues to produce this hormone until you eat enough food to literally fill your stomach and stretch the stomach wall. Farther down the line, in your intestines, levels of several hormones rise to varying degrees–depending on the nature of your meal–either inducing more hunger or turning off hunger. (FPD, p. 4-5)

Katz claims that by “organizing” the flavors in our diet, we can manipulate this chain of chemical and  signals and “subdue the appetite center in your brain sooner, before you’ve overeaten.” (p. 9) Katz also does acknowledge a role for insulin in controlling blood sugar, and points out that fast carbs cause a rapid blood sugar surge and an insulin spike which tends to overshoot and lead to a drop in blood sugar, whereas low glycemic carbs like oatmeal result in a lower rise in blood sugar, a slower release of insulin, “no rapid surge and dip in blood sugar levels” and sustained satiety.  But he does not make any direct connection between flavor and the insulin response, putting the onus on the neurochemical triggers like opioids, neuropeptide Y, and ghrelin.

The FPD establishes how flavors can begin a cascade that induces appetite. Katz is probably correct that the effects of individual flavors have a saturating effect on this response, and that the response can be increased by combining multiple flavors. I think that Katz overstates the role that neurotransmitters and leptin play in hunger and appetite.  Neurotransmitters and leptin are are important as primarily signaling compounds to the brain, but they are not the primary causal agent in that chain. Insulin is much more directly involved in the control of appetite, because it is insulin that reduces blood sugar to physiologically unsustainable levels in the first place, and the signaling compounds are merely the messengers. Blaming these signalling compounds for hunger is like blaming a witness for the crime. Perhaps neuropeptides and leptin can signal hunger without concurrent insulin response. I think this is unlikely, but if it occurs, I suspect it is because these signals have independently become classically conditioned to respond to flavors and other food cues that have become associated with the presence of food. As with insulin, these neurotransmitter responses to sensory stimuli can be deconditioned upon experience. However, Katz treats the neurochemical responses to flavors as “hardwired”, overlooking the fact that they are learned or conditioned responses.  The responses will strengthen if reinforced by eating food that increases blood sugar, and will weaken if not reinforced. His claim that sugar and fat alone cause the release of opioids into the bloodstream is not documented and seems unlikely. The tongue does not detect sugar and fat directly. In fact, some neurological research by Woolley et al at UCSF indicates that it is flavors, and not the macronutrient content of foods, that stimulate opioid secretion by the nucleus accumbens in the brain. To the extent that the hypothalamus is engaged, it requires a detectable signal such as flavor.  As Teff showed (see Diet page), the tractus solitarus will trigger the vagus nerve to secrete insulin only in response to flavor and scents that it has learned and expects to be associated with blood-sugar raising foods.

Sensa tastants.  Closely related to the Flavor Point diet is the use of tastants as Alan Hirsch has developed for his Sensa Weight Loss Program.  The Sensa tastants are intense non-caloric flavors that are sprinkled on foods to enhance flavor intensity.  The tastants are matched the flavor class of the foods: savory tastants are sprinkled on savory foods, while sweet tastants are sprinkled on sweet foods. The principle of sensory-specific satiety is identical with that of the Flavor Point diet. One is still advised to eat only one or two “flavor categories” of food at a meal. The advantage of Sensa over FPD, perhaps, is that the satiating “flavor point” is reached earlier in a meal, with less food and fewer calories consumed than otherwise.  It seems to me the the same result could be achieved by spicing your savory foods and adding non-caloric sweeteners to your desserts.

As with FLP, however, tastants will do nothing to fundamentally alter or extinguish strong flavor-insulin responses. So one remains vulnerable to a strong appetite returning when combining foods, and has to observe the principle of limiting the number and variety of flavors at any given meal.

The bottom line, with both FLP and Sensa, is that by confining yourself or intensifying a single flavor, you allow the insulin response to that specific flavor to saturate earlier, thereby limiting the appetite-inducing property of insulin.  If you were to add more successive different flavors, you will tend to stimulate separate flavor-detection pathways and add another wave of insulin secretion and stoking of appetite.

Odor inhalers (Scentsational Weight Loss). Direct exposure to saturating levels of food aromas is yet another way to exploit the sensory specific satiety mechanism. Even though it exploits the same mechanism, it is in an entirely different class and–as I will argue–odor inhalers have the potential to engender long term appetite deconditioning and weight loss.

Alan Hirsch describes his discovery of this phenomenon in his book Sensational Weight Loss (SWL), and the same concept is exploited in the commercial “diet pens” sold by SlimScents. There are a number of other related pens and inhalers marketed as “aromatherapy”. Hirsch reports a remarkable conclusion from his six month study of the use aroma devices for to quell appetite and spur weight loss. The study included 3193 participants, 86% of whom were women, and most of whom were significantly overweight (average weight = 217 lb.). Participants were given small odor inhalers, similar to lipstick dispensers, containing pleasant smelling substances. Three aromas were used: green apple, peppermint, and banana. Hirsch found that varying the aromas was more effective than sticking with the same aroma. Participants were asked to open and sniff the aromas whenever they got hungry–three sniffs in each nostril. But otherwise there were no forbidden foods or other dietary restrictions. The results were impressive. The average weight loss was 5 pounds per month.  Some people lost more than 100 pounds over the six month study. What is especially interesting to me, however, is that there was a permanent deconditioning effect, along the lines of the Deconditioning Diet (see Diet page).  Here are Hirsch’s comments regarding “deprogramming” of the participants’ learned responses to flavors, leading to long-term changes in eating habits:

Just as we have learned to respond to the smell of certain foods by feeling hungry and wanting to eat, we can, in a very real sense, “unlearn” or deprogram ourselves. For many people the smell of any food triggered hunger. Smell a doughnut, salivate; smell a pizza, and the stomach growls. Actually, most of us experience this much of the time; but in the overweight person, this conditioned, or learned, response can be quite. powerful. It’s exciting to realize that people can recondition themselves to smell an odor and not respond with hunger. In the absence of a food associated with the smell, hunger disappeared, the desire to eat subsided, and a pattern was broken. In many cases, this was a long-standing pattern that was broken during the six month study. (SWLP, p. 33-4)

Further evidence of a long term change was reflected in the frequency of use of the odor  devices during the study. At the beginning of the study, participants reported needing to sniff 200 times a day or more; by the end of the study, only occasional sniffing was needed to keep appetite in check. So the the aroma devices don’t themselves become habit forming–the dependence actually decreases over time as new eating habits are consolidated.

In Chapter 4 of Scentsational Weight Loss, Hirsch provides some additional advice, namely that we pre-saturate our satiey centers by sniffing our meals before the first bite to letter the odor molecules fully stimulate the olfactory bulb.  He recommends that we slowly chew and savor the flavor of each bite in order to “fool” the hypothalamus into “believing that more food has been ingested than is actually the case. He also recommends eating food warm or hot to maximize the aroma, adding spices whenever possible, and choosing the more strongly flavored versions of foods.  ”For example, if you eat popcorn, eat the cheese-flavored varierty, or choose an onion bagel over a plain one.” (SWLP, p. 62).

On the face of it, this advice is diametrically opposed to that of Seth Roberts’ Shangri-La Diet!  Roberts argues that blander foods induce weight loss, whereas Hirsch is arging for more intensely flavored and spiced foods. Who is right and what gives?

Here is where all three diets — SLD, FPD, Sensa, and SWL– come together.  After promoting the enhancement of flavor, Hirsch adds:

Try limiting your food choices at any one meal. We still encourage variety, but not necessarily all at one time. We have found that people who want to lose weight should eat only two or three different foods during a meal rather than eating a little bit of many foods…Avoid buffet tables and “all you an eat” food bars. Even salad bars can be dangerous…Even with a smell device, too many selections and unlimited choices spell potential overeating. (Sensa Weight Loss Program, p. 63-64)

…………………………………………………………………………………………………………………………………………………………………………..

A Unified Explanation of Flavor Control Diets. Here is my summary explanation that can account for the observed effects of all four dietary approaches:  Familiar flavors can induce a pre-prandial insulin response which leads to increased appetite and weight gain. This preprandial insulin response saturates separately for each basic flavor type (savory, salty, sweet, etc.). This saturating pre-prandial insulin response is is a learned response, and one that is reinforced only if it results ultimately in a rise in blood sugar and psychological satiation. If that flavor or aroma is not followed by more eating, it will eventually diminish or extinguish as a cue.

Here then is how this explains each of the four flavor control diets:

1. SLD explanation. Eating foods that contain carbohydrates (and to a lesser extent, proteins) with strong, familiar flavors will lead to a rapid pre-prandial insulin response which may be enough to cause a dip in blood sugar, stoking hunger and leading to further eating. Eating a small amount of bland or flavorless carbohydrate will satisfy hunger by slightly raising blood sugar, and will induce only a small post-prandial insulin response, insufficient to cause a rapid decline in blood sugar, so appetite will remain suppressed.  While SLD keeps insulin in check, it does so only so long as flavor cues are not present. But SLD does nothing to weaken the connection between familiar flavors stimuli and their insulin response, it merely eliminates the stimuli.  One would expect appetite to return when the familiar flavors are re-introduced.
2. FPD explanation. Eating foods with familiar flavors will induce two insulin responses:  a small pre-prandial response and a larger post-prandial response.  However, the pre-prandial insulin responses for that flavor peaks within about 4 minutes after exposure, and sensory detection of that flavor will rapidly saturate.  After it saturates, any further exposure to that specific aroma (or aroma class) will not induce any further insulin response for an extended period of time — up to about an hour. However, introducing new flavors, aromas or other food cues will cause additional secretion of insulin, increasing appetite. The more intense the flavor or aroma, the faster the saturation.
3. Sensa explanation.  The explanation for Sensa is the same as that for the FPD.  Activation of a sensory response to a flavor will induce a small and rapid pre-prandial insulin response. For a single flavor or aroma class, the detection of that flavor will saturate after a certain amount of time, after which it will not prompt any further insulin response.  If multiple aromas are sniffed, then all those smell receptors will become saturated, after which any further pre-prandial insulin response will become muted. Since the Sensa tastants contain no or minimal calories, they provide a way to reach flavor saturation faster, with fewer calories.  In that way, the use of tastants is more effective than the Flavor Point Diet, since fewer net calories are consumed while satisfying one’s appetite.
4. SWL (odor inhalants) explanation. With sensory-specific satiety approahes like FPD and Sensa, the stimulus-response relationship between flavor and pre-prandial insulin response is reinforced. The stimulus may saturate, but the connection with the insulin response remains in place, so that at subsequent meals, the flavor will induce pre-prandial insulin.  However, with SWL, the relationship between flavor and pre-prandial insulin is not reinforced, so it extinguishes!  This is a crucial difference. For this reason, SWL is actually a deconditioning diet that results in long term changes in the flavor-insulin response that suppress appetite and lead to weight loss.  Eventually, the aroma inhalers are no longer needed, or only rarely, to maintain the “deprogramming” that Hirsch alludes to.  By contrast, SLD, FLP and Sensa are not deconditioning diets, but merely methods of suppressing or limiting appetite that work by either minimizing or saturating the stimulus of food cues, but doing nothing to weaken the flavor-insulin response.

Lessons learned. Where does this leave us?  There is a lot to be learned from all four flavor control diets. Flavors and aromas that become associated with foods, particularly carbohydrate-containing foods, strengthen the insulin-response to those flavors and aromas, increase appetite, and tend to increase the consumption of those foods, leading to weight gain. This insulin response and the resulting appetite can be significantly dampened by limiting the variety of flavors while eating.  However, a much larger benefit is possible by using flavors to decondition your appetite:

• You can expose yourself to flavors without carbohydrates or other insulinogenic foods and this will dampen the flavor-insulin response, and lead to a decrease in appetite that is induced by food cues.
• By exposing yourself to a variety of flavors or aromatic stimuli without eating, you will saturate a fuller range of satiety centers and even more effectively block an insulin response.  Sniffing a variety of aromas of different types–savory and sweet– without eating can be helpful in curbing appetite.

These findings have been incorporated into the second phase of the Deconditioning Diet, as described on the Diet page in this website.

Please leave a comment.  You can also check out (and maybe start) a discussion on the Diet Forum linked to this blog.